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Drug Improves Cognitive Functioning in Patients with Secondary Progressive MS

By Frieda Wiley

Researchers have found that administering a drug for multiple sclerosis (MS) significantly improves cognitive processing speed in patients who have secondary progressive MS compared with placebo, according to a new study. 

The medication, known as siponimod, demonstrated clinical benefit over placebo, with an estimated hazard ratio of 0.79 (95% CI:0.65-0.95), or a relative risk reduction of 21%.


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“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,” said study author Ralph H. B. Benedict, PhD, a professor of neurology at the Jacobs School of Medicine and Biomedical Sciences at the University of Buffalo in New York, and colleagues.

Siponimod modulates the sphingosine-1-phosphate (S1P) receptor. The drug exhibits specificity for the S1P1 and S1P5 subtype and easily crosses the blood brain barrier. Siponimod reduced confirmed disability progression in patients who have progressive MS when compared with placebo. Researchers posit that the drug may directly reduce inflammation and promote remyelination in the central nervous system.

“The overall findings from this study in a population with advanced neurological disability suggest that treatment with siponimod beneficially impacts cognitive functioning as measured by the Symbol Digit Modalities Test, a benefit likely to have a high impact on quality of life and vocational status,” the study’s authors wrote.

The overall findings from this study in a population with advanced neurological disability suggest that treatment with siponimod beneficially impacts cognitive functioning as measured by the Symbol Digit Modalities Test.

The study was published online December 16, 2020, in Neurology.

The neurodegenerative effects of MS compromise cognitive function, which can hinder patients’ ability to conduct activities of daily living, drive, hold gainful employment, and even shop online. Patients with progressive forms of the disease tend to experience these signs more severely.

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Researchers evaluated the safety, efficacy, and tolerability of siponimod in comparison with placebo in patients with secondary progressive MS in EXPAND, a double-blind, parallel-group, placebo-controlled, event- and exposure-driven phase III trial. The study’s primary objective was to evaluate the effectiveness of siponimod compared with placebo in delaying the time to 3-month confirmed disability progression — a value measured by the expanded disability status scale (EDSS). Researchers defined a 3-month confirmed disability progression as an increase from EDSS baseline subsequently confirmed after at least 3 months. The rheumatology community holds the general consensus that the Symbol Digit Modalities Test is the best available tool to measure cognitive processing speed in studies conducted in MS. The Symbol Digit Modalities Test is also the only current test of cognitive processing speed deemed “clinically meaningful.”

In the study, investigators randomized 1,651 patients 2:1 to receive either siponimod 2 mg/day or placebo. Researchers halted doubled blinding once patients experienced a predefined number of disability progression events and after more than 95% of patients had been subjected to randomization for 1 year. Those patients with confirmed disease progression were given the option to switch to open-label siponimod therapy as a rescue medication or to cease treatment altogether with or without initiating another disease-modifying drug.

Eligibility criteria included age of 18 to 60 years, diagnosis of secondary progressive MS and progression on the EDSS in the previous 2-year period, and having an EDSS score of 3.0 to 6.5 at the time of screening.

Dr. Benedict and colleagues found that on average the group of people taking siponimod improved their scores on the Symbol Digit Modalities Test after 1 year, 18 months, and again at 2 years, compared with the group of people taking placebo, in whom the score stayed the same.

Those patients taking siponimod had a 28% higher chance of having a sustained improvement of four or more points compared with those taking a placebo. An increase or decrease of four or more points is considered clinically meaningful and is associated with quality-of-life outcomes and disability progression. Patients taking siponimod also had a 21% lower chance of having a four-point or lower decrease in score.

Among all participants, 35% of people taking siponimod improved their scores by four or more points compared with 27% of people taking placebo, 41% taking siponimod had no change compared with 42% taking a placebo, and 25% taking siponimod had lower scores by four or more points compared with 32% of people taking a placebo.

Scores on two other thinking and memory tests did not differ between the two groups.

We are impressed to see that siponimod may improve cognitive processing speed in people with MS.

Nearly 20% of patients in the placebo group and roughly 10% percent of patients in the siponimod group switched to open-label siponimod treatment. The placebo group had 135 patients opt to cease treatment; 57 patients in the siponimod group ended treatment. 

“We are impressed to see that siponimod may improve cognitive processing speed in people with MS, however more research is needed to confirm our results,” said Dr. Benedict.

He cautioned, “Because we did not see changes on two other cognitive tests, more research should further examine how siponimod affects scores on a broader array of thinking and memory tests. This research is needed before prescribing siponimod for cognition can be considered.”

Side effects that occurred more frequently in patients taking siponimod versus placebo included high blood pressure, higher levels of liver enzymes, eye swelling, shingles, and convulsions.

 One feature of the study design that distinguished it from other MS studies that evaluate neuropsychological properties is that investigators did not prescreen trial enrollees or exclude them for various conditions known to alter the cognitive development and cognitive abilities. Examples of such conditions include childhood learning disabilities as well as neurological and psychiatric disorders such as bipolar disorder and traumatic brain injury. For this reason, the study conveys the advantage of reflecting what the study’s authors refer to as “a typical secondary progressive MS population.” This distinguishing feature, however, comes with the risk of creating potential biases resulting from the inclusion of patients who exhibit these traits. 

A limitation of this study is that researchers collected no demographic data such as educational background or presence of common MS symptoms such as fatigue, depression, or visual impairment as the primary outcome of the study.

The study was funded by Novartis Pharma AG, maker of siponimod. Dr. Benedict has consulting and speaking relationships with Novartis.