What’s New in MS Research – May 2021

Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD

The remarkable breadth of the questions that scientists are investigating as they seek to better understand and treat multiple sclerosis is on full display in this edition of “What’s New in MS Research.”

Drawing on abstracts presented at last month’s annual meeting of the American Academy of Neurology (AAN), which was conducted virtually from April 17-22, 2021, this iteration of “What’s New in MS Research” covers topics including racial and ethnic differences in MS presentation and treatment response, an app for dealing with MS-related anxiety, and promising results from a Phase II trial of the investigational agent IMU-838. Factors predicting the persistence of COVID-19 symptoms in people with MS, as well as the links between MS severity and the prevalence of other health conditions, are also examined.

Several AAN abstracts reported below provide longer-term data on the efficacy and safety of recently approved disease-modifying therapies (DMTs.) In those and other research items covered here, the central role of magnetic resonance imaging (MRI) in assessing treatment response and predicting disease course is highlighted.

Beyond the positive or negative nature of any single study or development, however, the sheer breadth of research being conducted in MS is reason to be confident that substantial further progress awaits in 2021 and beyond. Drawing from studies published in peer-reviewed journals, presentations given at the September 2020 joint meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), corporate press releases, and other sources, this installation of “What’s New in MS Research” provides positive news during challenging times.

Do you and your neurologist attach the same importance to various DMT benefits and risks?

The potential benefits of MS therapy that matter most to patients, and the possible side effects that cause them the greatest concern, are not necessarily the same benefits and side effects that neurologists consider most important.

That’s the finding of a recent study involving 150 people with relapsing-remitting MS and 150 neurologists who treat the condition. The patient group was 84% female and had a mean age of 54 years. None of the patients had received a disease-modifying therapy (DMT) typically prescribed for advanced forms of relapsing MS. Two-thirds of the neurologists were in private practice. Both groups participated in an online survey in which they chose between two treatment profiles that featured seven attributes – including both benefits and adverse effects – of DMT therapies.1

Reducing the rate of brain volume loss (BVL) was the benefit that won top ranking from patients, while risks of infection and flu-like symptoms were the possible side effects that mattered most to them. By contrast, neurologists were most concerned with reducing the risk of a life-threatening side effect, followed by slowing disability progression over two years and infection risk. Patients and physicians alike accorded the least importance to reducing the one-year relapse rate and risk of gastrointestinal symptoms.

The distinct benefit/risk profiles of various DMTs give people with MS and their clinicians an unparalleled opportunity to match treatment choice to a patient’s medical needs, risk tolerance, and goals of therapy. As this study underscores, however, a critical prerequisite to such shared decision-making is for the patient and clinician to discuss which potential benefits and side effects matter most to each of them, and why.

Characteristics and clinical outcomes of underserved minority patients with multiple sclerosis

Black/African-American people with MS have greater pre-treatment disease activity and higher on-treatment relapse rates than white people, according to a study involving more than 1,000 patients. The study found similar differences between Hispanic and non-Hispanic people with MS in terms of disease activity prior to starting treatment, but only a modest, non-statistically significant difference with regard to relapses while on therapy.2

Investigators analyzed data on MS patients treated with the disease-modifying therapy (DMT) interferon beta-1a at MS centers belonging to the MS PATHS network. Looking at several measures of disease course and treatment impact, they compared the experiences of 81 Black/African-American patients with those of 866 white patients, and also examined how the experience of 29 Hispanic patients contrasted with that of 560 non-Hispanic patients.

The proportion of Black/African-American patients who had experienced two or more relapses in the year prior to starting treatment was twice that of white patients (32.1% vs 15.7%). Similarly, 34.5% of Hispanic patients had experienced two or more relapses in the year before they began treatment, as opposed to 18.4% of non-Hispanic patients. After they began taking a DMT, Black/African-American patients had an average annual relapse rate (ARR) that was twice that of white patients (1.26 vs 0.64), and the difference was statistically significant. There was less difference in ARR between the Hispanic and non-Hispanic subgroups (0.92 vs. 0.64), and that difference was not statistically significant.

Differences were also seen between the groups in various MRI measures of disease burden, with the findings generally being worse in the minority groups.

As society strives to reduce inequities in health care, identifying differences in disease presentation, treatment, and outcomes is an important prerequisite for understanding and addressing the underlying causes. As the study’s authors concluded, “These results highlight the need for closer observation of MS minority patients to improve treatment outcomes.”

MRI findings yield clues to likelihood of MS worsening in pediatric patients

“What does the future hold for my child?” This is one of the questions foremost in the minds of parents whose child has been diagnosed with pediatric-onset multiple sclerosis.

While clinicians cannot fully predict the course of MS for any patient, regardless of age, a study by Italian investigators suggests that MRI findings at baseline and monitoring during the first two years after diagnosis can provide a wealth of information about likely developments over the next nine years.3

The research showed that identification of optic nerve lesions on MRI at diagnosis was associated with shorter time to first relapse and significantly increased risk for experiencing disability worsening within nine years. Detection of two or more new T2 lesions in the first two years after diagnosis was associated with an almost five-fold risk of disability worsening after nine years, relative to young people with MS who did not develop multiple lesions in that post-diagnosis period. The presence of cervical cord lesions at diagnosis was predictive of worse outcomes over time, with the likelihood of a higher Expanded Disability Status Scale (EDSS) score nine years later, hence increasing with the number of such lesions identified at baseline.

The investigators, who based their findings on 123 pediatric MS patients followed over nine years, observed, “A complete baseline MRI assessment and an accurate clinical and MRI monitoring during the first two years of disease have proven to represent powerful tools to predict pediatric multiple sclerosis patients’ long-term prognosis.”

Young and stressed over MS? There’s an app for that…

Being diagnosed with MS is distressing at any age, but receiving the news when you’re in your twenties or even younger carries a particular set of worries, including concerns about many near- and long-term plans and dreams potentially being upended.

A team of researchers based in New York City recently explored whether harnessing young people’s affinity for apps could help in addressing the anxiety and depression that can accompany living with MS. The short answer to that question: Yes!4

The study involved 22 people diagnosed with pediatric-onset MS. Eighty-six percent were female, and the participants ranged in age from 15 to 23 years, with an average age of just under 18 years. They had a minimal degree of disability. The participants were provided with the Personal Zen app, which facilitates use of cognitive bias retraining, and were instructed to use the app at least five times per week for four weeks. The researchers measured participants’ anxiety and stress levels at baseline and each subsequent week.

At the end of the study, there were significant decreases in anxiety, as measured by the Beck Anxiety Inventory; depression, as assessed by the Beck Depression Inventory; and negative affect. Further, study participants averaged 16.6 entries over the course of the month-long study, an adherence rate that researchers said showed that the app is not only effective but also a feasible intervention for reducing distress in young people with MS.

Which people with MS are most likely to have persistent COVID-19 symptoms?

One of the many maddening mysteries swirling around COVID-19 is the question of why some people who contract the viral infection recover completely while others experience lingering symptoms months after first becoming ill. A team of British researchers recently examined factors that may affect recovery from COVID-19 in people with multiple sclerosis (MS).5

The investigators surveyed 391 people with MS who reported having had COVID-19. Seventy-six percent of the participants said they had fully recovered from their infection, while 16% said they had mostly recovered, and 8% were still experiencing symptoms.

The study participants’ demographic factors did not have an impact on the likelihood of reporting complete recovery. Neither did several factors related to MS, including use or non-use of a disease-modifying therapy, MS duration, or type of MS. However, people with a higher score on a web-based version of the Expanded Disability State Scale (EDSS) and those who reported physical issues related to MS on the Multiple Sclerosis Impact Scale-29 were less likely than others to report a full recovery. Further, experiencing anxiety in the year prior to the pandemic increased the likelihood that a study participant would report persistent symptoms of COVID-19.

Examining the ties between MS symptoms, severity, comorbidities, and medical costs

The greater the severity of a person’s MS, as determined by symptoms, the more likely he or she is to have other serious health conditions. That was one of several findings to emerge from an analysis of healthcare claims data involving more than 1,000 people with MS.6

The study’s authors categorized a person as having mild, moderate, or severe MS based on the presence or absence of related bladder/bowel, psychiatric, cognitive, and physical-function symptoms. They then looked at the proportion of patients in each group who had claims-data evidence of other serious health conditions, including gastrointestinal disease, chronic lung disease, hypertension/hyperlipidemia/diabetes, and substance use disorder, among others.

In all cases, the proportion of people with a comorbid condition increased with the severity of MS. For example, 4.5% of people with mild MS had chronic lung disease, compared with 12.4% with moderate MS and 13.5% with severe MS. Similarly, the prevalence of a substance use disorder was 1.7% in the mild MS group, 4.3% among people with moderate MS, and 5.2% in the severe MS group. With both of those comorbid conditions, and all of the others examined, the differences between groups were statistically significant.

The researchers also found that direct medical costs increased with MS severity, from a mean average per year of $9,921 in the mild MS group to $21,326 for those with moderate MS, and $34,912 for people with severe MS.

Researchers: Study findings warrant Phase III trials for IMU-838

The results of a Phase II trial of the investigational agent IMU-838, also known as vidofludimus calcium, show the value in proceeding to Phase III clinical trials, researchers said recently.7

IMU-838 is an oral agent that inhibits dihydroorotate dehydrogenase (DHODH), an enzyme believed to play a role in the development of MS. The Phase II EMPhASIS trial was conducted at 36 centers in four European countries, and enrolled 210 people with relapsing MS. Those patients were randomized to receive once-daily oral doses of 30 mg of IMU-838, 45 mg of IMU-838, or placebo.

After 24 weeks of treatment, patients taking the 30-mg dose of IMU-838 had 70% fewer combined unique active (CUA) lesions on MRI than their counterparts receiving placebo, while patients taking the 45-mg dose of the medication had 62% fewer CUA lesions than those in the placebo arm. Meanwhile, the annualized relapse rate was 0.39 in the IMU-838 30-mg group, 0.48 in the 45-mg group, and 0.53 in the placebo group. The most common treatment-emergent adverse events reported were headache and nasopharyngitis (cold and sore throat symptoms).

Commenting on those results, the study’s authors concluded, “Further assessment of this next-generation DHODH modulator in Phase III clinical trials is warranted.”

Mayzent® (siponimod) demonstrates long-term benefits in secondary-progressive MS

The disease-modifying therapy (DMT) Mayzent® (siponimod) showed a beneficial effect on brain volume loss for up to five years among people with secondary-progressive multiple sclerosis (SPMS), researchers reported recently.8

Mayzent is a once-daily oral medication approved in 2019 for the treatment of relapsing forms of MS and active SPMS in adults. The Food and Drug Administration approved Mayzent on the basis of data that included results from the Phase III EXPAND study, which compared Mayzent to placebo in terms of disability progression, cognitive decline, and MRI measures in people with SPMS.

At the conclusion of the main EXPAND study, participants who had received Mayzent and those had been assigned to the placebo group were given the option of continuing on in an extension study in which all participants would receive the DMT. Of the 1,651 patients who completed the main study, 1,224 chose to enter the extension study.

Investigators used MRI to assess changes in brain volume among those who had received the medication from the start of EXPAND (continuous group) and those who switched to Mayzent in the extension study after having received placebo initially (switch group).

At the five-year mark, there was significantly less whole brain volume loss in the continuous group than the switch group (-1.62% vs -1.76%, p<0.05). People who had received Mayzent from the start of EXPAND also had significantly less volume loss in the thalamus compared to people who initially had received placebo (-2.68% vs. -3.48%, p<0.0001), while the low rate of volume loss in cortical grey matter in the two groups was similar.

The study’s authors concluded, “Siponimod treatment showed sustained efficacy on MRI measures including GM [grey matter] atrophy over the long term, and benefit upon switching from placebo. Persistent differences between continuous and switch groups in measures of brain integrity highlight the importance of early treatment initiation.”

Measuring the impact of Vumerity® (diroximel fumarate) over two years

People with relapsing-remitting multiple sclerosis (RRMS) taking the disease-modifying therapy Vumerity® (diroximel fumarate) had annual rates of brain volume loss over two years that were comparable to the upper limit of loss seen in healthy adults.9

That finding is one of the main interim results to emerge from a post hoc analysis of 396 patients with RRMS who participated in the EVOLVE-MS-1 study of Vumerity, a once-daily oral medication approved by the Food and Drug Administration in 2019.

Investigators reported that the mean percent brain volume change among patients receiving the medication was -0.36% from baseline to Week 48, and -0.35% from Week 48 to Week 96. By contrast, they noted, healthy adults experience a -0.1% to -0.35 change in brain volume each year.

Additionally, 94.3% of patients did not have confirmed disability progression (CDP) at Week 48, and 90.7% were free of CDP at Week 96. Further, at Week 48, 44.7% of study participants had no evidence of disease activity (NEDA) as measured by absence of relapses, no disability progression over a 12-week period, and MRI findings. One-quarter of participants met the NEDA criteria at Week 96.

ENSEMBLE study: Ocrevus® (ocrelizumab) shows benefit over one year in relapsing MS

More than 80% of patients with early-stage relapsing-remitting multiple sclerosis (RRMS) who took Ocrevus® (ocrelizumab) as their first disease-modifying therapy had no evidence of disease activity (NEDA) at 48 weeks, according to interim data from the Phase IIIb ENSEMBLE study.10

The study involved 678 patients, two-thirds of whom were female. The patients’ mean age was 32.4 years and, on average, the study participants had been experiencing MS symptoms for a little over one year. Their average baseline Expanded Disability Status Scale (EDSS) score was 1.71, as measured on a scale from 0 to 10, with a higher score indicating worse disability.

NEDA is a composite measure of MS activity that considers relapses, disability progression, and MRI findings. Ninety-one percent of study participants had NEDA at 24 weeks, while 84.8% met the criteria at 48 weeks. Meanwhile, the adjusted annualized relapse rate at 48 weeks was 0.0005 (a rate of 1 represents 1 relapse per year), and the average EDSS score remained stable at Week 24 and Week 48. Additionally, age-adjusted blood levels of serum neurofilament light chain, a marker of damage to certain nerve cells, declined from 10.5 pg/mL at baseline to 4.55 pg/mL at Week 48, as compared with 4.12 pg/mL in age-matched healthy controls. Safety findings were consistent with those in other studies of the medication.

The study’s authors noted, “Treatment-naïve patients with early-stage RRMS in ENSEMBLE responded consistently well to ocrelizumab treatment based on clinical, MRI, and biomarker measures; no new safety signals were observed.”

MRI-based study shows early onset of action for Mavenclad® (cladribine)

Mavenclad® (cladribine) reduced the counts of combined unique active (CUA) lesions in people with relapsing forms of MS within six months of treatment initiation, researchers reported recently.11 Further, the improvement in this MRI-based measure of MS was seen in patients with high relapse activity as well as in those without such activity, and in both treatment-naïve patients and those who previously had received another disease-modifying therapy.

The findings, which emerged from a subgroup analysis of the MAGNIFY-MS study, compared the CUA count at baseline with counts for time periods extending up to six months after initiation of Mavenclad, an oral medication that in 2019 received Food and Drug Administration approval for use in relapsing MS. The study’s authors noted that the results demonstrated the medication’s early onset of action.


1 Kumar J, Will O, Tencer T, et al. Patient and neurologist preferences in the US for RRMS treatments: Findings from a discrete choice experiment. AAN 2021 [P15.058].

2 Hersh CM, Fitzgerald K, Zhovits Ryerson L, et al. Characteristics and clinical outcomes of underserved minority patients with multiple sclerosis treated with peginterferon beta-1a or intramuscular interferon beta-1a in MS PATHS. AAN 2021 [P15.169]

3 De Meo E, Bonacchi R, Moioila L, et al. Early clinical and MRI predictors of long-term disability in pediatric multiple sclerosis patients. AAN 2021 [S28.005].

4 George A, Cho H, Krupp L, Dennis T, Charvet L. A digital tele-health intervention for anxiety and stress management in younger patients with MS. [P15.180].

5 Garjani A, Nicholas R, Middleton R, et al. Determinants of recovery from the coronavirus disease 2019 in people with multiple sclerosis: The UK MS Register COVID-19 Prospective Cohort Study. AAN 2021 [S28.003].

6 Hendin B, Brook R, Beren I, et al. Assessing presence of MS-related symptoms as a proxy for disease severity in multiple sclerosis using administrative claims data. AAN 2021 [P15.241].

7 Fox R, Wiendl H, De Stefano N, Sellner J, Muehler A. Efficacy and safety of the selective oral DHOHD modulator vidofludimus calcium (IMU-838) in relapsing multiple sclerosis (EMPhASIS): a randomized, placebo-controlled phase 2 trial. AAN 2021 [P15.085]

8 Arnold DL, Kappos L, Vermersch P, et al. Long-term effect of siponimod on MRI outcomes in SPMS: analyses from the EXPAND study up to 5 years. AAN 2021 [P15.083]

9 Oh J, Arnold DL, Singer BA, et al. Effects of diroximel fumarate on brain volume change and disability progression in adults with relapsing-remitting multiple sclerosis from EVOLVE-MS-1. AAN 2021 [P15.097].

10 Vollmer T, Freedman MS, Killestein J, et al. Recently diagnosed early-stage RRMS: NEDA, ARR, disability progression, serum neurofilament and safety: 1-year interim data from the ocrelizumab Phase IIIb ENSEMBLE Study. AAN 2021 [P15.099]

11 De Stefano N, Barkhof F, Montalban X, et al. Reduction in CUA MRI lesions in the first 6 months after cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS subgroup analysis. [AAN 2021 [P15.072].

12 Kaisey M, et al. Preventing multiple sclerosis misdiagnosis using the “central vein sign”: A real-world study. ECTRIMS 2020 [P0135].

For More Information

For general information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.

Written by Tom Garry, Medical Writer
Reviewed by Dr. Barry Hendin, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer