What’s New in MS Research – July 2022
Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD
Hope filled the halls of the Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) during the first week of June, when MS clinicians, researchers, and advocates from across the country and abroad convened to exchange the latest findings in MS research.
That gathering provided a forum for the presentation of hundreds of studies on investigational medications being developed for the treatment of relapsing and progressive forms of MS, long-term data on FDA-approved therapies, advances in diagnosis and symptom management, and new findings on the causes and course of MS.
Summaries of key findings on several investigational and approved medications appear below. Other items in this edition of “What’s New in MS Research” might be categorized under the rubric of “If you feel something, say something.” Those reports include information on people who waited a year or more to talk with their clinicians about spasticity, reluctance to seek help for restless leg syndrome, and a frequent mismatch between clinicians’ perceptions of how often patients are experiencing various MS symptoms and how many people with MS are actually living with fatigue, depression, difficulties concentrating, and other challenges.
If MS were an unsolved crime, Epstein-Barr virus (EBV) would be a “person of interest.”
As researchers continue to do painstaking medical detective work to untangle the mystery of what causes MS, EBV is often seen lurking about, its presence well documented but its culpability unclear. Further, not only EBV but other herpesviruses, such as herpes simplex virus types 1 and 2 (HSV1 and HSV2), have been suspected of playing a role in the development of MS.1
Investigators explain, “Herpesviruses have 4 unique routes for infection and latency in the central nervous system: olfactory nerve retrograde axonal transport, peripheral anterograde axonal transport from the trigeminal ganglia, dispersion from latent reactivation, and hematogenous transport. Combined with the ability of [herpesviruses] to ‘reactivate’ after acute infection, these routes allow the virus to associate chronically with neurons, astrocytes, and oligodendrocytes, which could lead to, or exacerbate, the neuroinflammation frequently observed in patients with MS.”
To get a better sense of how often EBV, HSV1, and HSV2 are found “at the scene” of MS, those investigators analyzed immunologic markers in blood drawn from neurology clinic patients between July 2018 and December 2021. Depending on the specific test, blood samples from 100 to 233 patients were evaluated. In each case, roughly half of the patients had MS while the remainder did not. The researchers found that:
- 99.1% of people with MS had a blood marker for EBV known as EBV capsid antigen, as opposed to 87.4% without MS, with the difference being statistically significant
- 97.8% of people with MS were positive for another marker for EBV, serum EBNA IgG, compared to 83.6% of people who did not have MS; again, the difference was statistically significant
- 46.6% of people with MS and 47% of the control group were seropositive for a marker of HSV1 infection
- 23.3% of people with MS and 28.4% of those without MS had a blood marker for HSV2
The study’s authors noted that, “These findings further support an association between EBV infection and MS, but not between HSV1 or HSV2 and MS.”
By further characterizing the links between MS and EBV, this study and similar investigations help guide the efforts of other research focused on therapies targeting EBV with the aim of altering the course of MS.
Two doses of an investigational stem cell therapy given eight weeks apart reduced the levels of four inflammatory biomarkers in the cerebrospinal fluid (CSF) of people with progressive forms of multiple sclerosis, although levels of another marker of inflammation increased, researchers report.2
NurOwn® (MSC-NFT) is a therapy that uses mesenchymal stem cells (MSC) from a patient’s bone marrow and induces them to secrete high levels of neurotrophic factors (NTF), molecules that support the growth, survival, and differentiation of neurons. It is being studied in a Phase II trial that has enrolled 20 people with progressive forms of MS.3 Study participants had baseline Expanded Disability Status Scale (EDSS) scores of 3 to 6.5. (The EDSS runs from 0 to 10, with a higher number reflecting a greater degree of disability.) To be eligible, participants also had to be able to walk 25 feet in 60 seconds or less, and to not have had a relapse in the six months before they enrolled in the trial.
The study participants were given NurOwn via lumbar puncture at weeks 0, 8, and 16, and then followed to week 28. CSF samples were collected at week 16, before administration of the third dose, and researchers measured the levels of several inflammatory biomarkers, including osteopontin (OPN), soluble CD27 (sCD27), and stromal-derived factor (SDF-1a). Earlier research has shown those biomarkers to be relevant to the natural history of progressive MS and treatment outcomes. Levels of monocyte chemoattractant protein-1 (MCP-1) and chitotriosidase (CHIT-1) also were measured.
Compared to baseline measurements, the researchers found reduced levels of OPN, sCD27, MCP-1, and SDF-1a in the subjects’ spinal fluid, although CHIT-1 levels were increased by an average of 18%.
Researchers continue to investigate the significance of various inflammatory markers in MS, and do not as yet have a clear understanding of how changes in levels of those markers may affect a person’s MS. Nonetheless, the reductions seen in several markers of inflammation, including three linked by earlier research to the course of progressive MS, is encouraging.
Ublituximab is an investigational medication being evaluated by the Food and Drug Administration (FDA) for the treatment of relapsing forms of MS. The medication is a monoclonal antibody that targets CD20, a protein found on the surface of B cells, which are white blood cells shown to play a role in MS. Ublituximab is given by infusion, with two initial doses administered 14 days apart, followed by infusions every 24 weeks.
In the Phase III ULTIMATE I and ULTIMATE II studies, people with relapsing MS who received ublituximab had a lower average annualized relapse rate (ARR) than others with relapsing MS who received an FDA-approved medication, Aubagio® (teriflunomide).
At the annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC) held in June, investigators presented additional data from ULTIMATE I and II focused on how ublituximab affects disease progression relative to Aubagio, which is a pill taken once a day.4
The researchers looked at pooled data on 549 people participating in ULTIMATE I and the 545 people in ULTIMATE II, which both had a 96-week study period. They found that:
- 15.3% of people receiving ublituximab experienced disability progression during any 12-week period of the study, as opposed to 25.3% of people receiving Aubagio
- Of those who did experience 12-week disability, those in the ublituximab group had less of an increase in disability, with their Expanded Disability Status Scale (EDSS) scores changing by an average 0.9 at week 96, as opposed to a 1.4 change in the Aubagio group
- Another study measure, time to confirmed or unconfirmed disability progression, also favored ublituximab, with the difference between people taking that medication and Aubagio being statistically significant
The FDA is evaluating data from the ULTIMATE I and II trials, as well as additional information it has requested from TG Therapeutics, the company developing ublituximab. The agency is scheduled to make a decision on approval to use ublituximab in relapsing forms of MS by December 28, 2022.5
Following up on a 48-week trial that yielded encouraging findings on evobrutinib – an investigational medicine being developed to treat relapsing forms of MS – a 2.5-year study found that the therapy showed continued efficacy, with no new safety signals emerging over the longer-term evaluation.6
Evobrutinib inhibits Bruton tyrosine kinase, an enzyme that plays a crucial role in the development of B cells, which, in turn, play a role in MS. In the 48-week study, 267 people with relapsing forms of MS received either placebo, one of three doses of evobrutinib, or dimethyl fumarate, an FDA-approved disease-modifying therapy.
At the end of the 48-week study, 213 participants, or 80% of the total, opted to enter the longer-term extension study. All patients in that study received 75 mg of evobrutinib once daily before progressing to 75 mg twice a day. Sixty-one percent of the original study’s patients completed at least 132 weeks of treatment in the open-label extension (OLE).
Seventy-eight percent of patients reported a treatment-emergent adverse event during the OLE study. However, it is important to remember that “treatment emergent” means that the event occurred while a person was taking the medication, not that the medication necessarily caused the event. By contrast, 59 people, or 27.7% of the group, had an adverse event that study investigators believed was related to treatment. Six of those treatment-related adverse events were considered serious.
Meanwhile, the available OLE data showed that the annualized relapse rate for study subjects who had received 75 mg of evobrutinib twice daily in the double-blind period was 0.12. That number reflects a person having one relapse over the course of roughly eight years.
A study involving almost 2,500 adults with relapsing forms of MS indicates that the oral disease-modifying therapy Zeposia (ozanimod) has a well-established safety profile and maintains its effectiveness for several years.7
DAYBREAK is an open-label extension study that includes people with MS who participated in four clinical trials that helped Zeposia secure FDA approval in March 2020. Of the 2,639 patients from the earlier trials who were eligible to enroll in DAYBREAK, 2,494 chose to participate in the long-term trial. Those people received 0.92 mg/d of Zeposia for an average of 46.8 months in the open-label extension study, with some individuals treated for up to 62 months, or slightly more than five years.
More than 2,143 of the participants, or 85.9%, reported at least one treatment-emergent adverse event (TEAE), with the events being similar in nature to those reported in the parent trials. Just under 12% had a serious TEAE, and 3% discontinued treatment due to a serious adverse event. Meanwhile, as of May 2021, 8.7% of patients reported a confirmed or suspected case of COVID-19. While 93% of those cases were non-serious, there were three deaths related to COVID.
Meanwhile, the adjusted annualized relapse rate over the average 46.3 months of treatment was 0.103, which represents one person having a relapse roughly every 10 years.
Based on those findings, researchers concluded that, “Interim data from patients in DAYBREAK treated for up to 62.7 months are consistent with the established safety profile of ozanimod and show sustained control of disease activity. The benefit/risk profile of ozanimod remains unchanged, with most COVID-19 cases being nonserious.”
People with early MS taking the oral disease-modifying therapy Ponvory (ponesimod) had roughly half the relapse rate of similar individuals taking Aubagio® (teriflunomide) in the Phase III OPTIMUM study, researchers report.8
In March 2021, the FDA approved Ponvory for the treatment of adults with relapsing forms of MS. The approval was based in part on the results of the OPTIMUM trial, which demonstrated that Ponvory reduced the annualized relapse rate (ARR) to a greater extent than Aubagio in people with MS who had Expanded Disability Status Scale (EDSS) scores of 0 to 5.5.
Researchers decided to take a closer look at people with earlier or milder MS, which they defined as an EDSS score of 0 to 3 and/or not having received a prior disease-modifying therapy (DMT). They found that in this subgroup, Ponvory had an even greater benefit relative to Aubagio than it did in the overall study population, with an ARR 47% lower than that of Aubagio, which also is an oral DMT. Ponvory also had a more favorable impact than Aubagio on MS-related fatigue in patients with an EDSS score of 3 or less and those who were treatment-naïve. (Individuals with MS who are “treatment-naïve” refers to those who have never previously taken a disease-modifying therapy.)
This sub-analysis of the OPTIMUM results addresses a timely issue in MS care. While a growing body of evidence shows that early administration of higher-efficacy DMTs, such as Ponvory, can have a favorable impact on long-term outcomes, many clinicians and patients favor a stepped approach, reserving more-potent medications for use later in the course of MS.
Weighing in on that topic, the study’s authors wrote that Ponvory “demonstrated increased clinical benefit compared with teriflunomide (Aubagio) in early disease subgroups and compared with the overall population. This subgroup analysis confirms the advantage of using ponesimod (Ponvory) as an early high-efficacy treatment.”
People with MS who switched their disease-modifying therapy (DMT) during a 12-month study period had lower adherence to their treatment regimen than people who remained on the same DMT, according to a recent study.9
The study examined adherence to self-administered therapy among 968 people with MS who filled three or more prescriptions at one of four health system-owned specialty pharmacies from January 2020 to June 2021. Three-quarters of the study participants were female, and 52% had commercial insurance. The study subjects’ median age was 51 years.
After adjusting for other variables, researchers found that people who did not switch their DMT during the study period were 3.8 times more likely to have a higher proportion of days covered (PDC), a widely used measure of adherence to treatment, than those who had at least one switch.
The researchers did not report on study subjects’ reasons for switching therapy – such as adverse effects or financial considerations – that may have had a lingering effect on people’s use of their new medications. They did note, however, that their findings may indicate a need for clinicians to monitor patients and their medication use following a change of therapies.
Four out of five people with MS participating in a recent online survey experience spasticity every day, with one-third of those people having constant symptoms.10
Those were among the main findings from the SEEN-MSS (Symptoms and Emotions Exploration Needed in Multiple Sclerosis Spasticity) survey, which was developed in collaboration with three MS advocacy organizations in the United States, including the Multiple Sclerosis Association of America (MSAA). Researchers used multiple-choice and rank-order questions to document participants’ experience with spasticity, explore their knowledge of the condition, and understand how they talked about it with their clinicians. The online survey was conducted from February through May 2021.
Seventy-eight percent of people completing the survey were female. The respondents’ average age was 56.8 years. They had been diagnosed with MS a mean 16.8 years earlier, and had experienced symptoms of spasticity for an average 11.5 years, or starting a little more than five years after receiving a diagnosis of MS.
Based on participants’ responses:
- 40% have multiple periods of spasticity each day
- 70% have varying degrees of spasticity severity over the course of a day
- 90% are not able to predict when spasticity will occur or how severe it will be
Just over half of respondents identified fatigue as a trigger for spasticity, while 49% cited physical activity, 45% said heat gave rise to spasticity, and 43% said stress played a role.
The evening was the worst time for spasticity for 31% of people, followed by the overnight hours (18%), morning (17%), and afternoon (4%). Thirty percent said the severity of their spasticity remained unchanged throughout the day.
Two-thirds of participants said that uncertainty about when and how severely they might experience spasticity prevented them from engaging in desired activities. One-half said they adjust the dose and frequency of their medications based on the severity of the symptoms they are experiencing that day. In keeping with that practice, the study’s authors noted, “The results emphasize that the variable nature of spasticity and its lack of predictability necessitate customizable treatments based on the severity and duration of spasticity symptoms.”
Those researchers also explored survey participants’ knowledge of the many ways the condition presents itself and how – and when – people with MS talk with their clinicians about spasticity.11
They found that:
- 65% of respondents felt not at all prepared or only minimally prepared for the possibility of spasticity despite having been diagnosed with MS
- 60% said they were confused by their symptoms and did not recognize them as spasticity
- 69% used the term “muscle spasms” to describe their symptoms, even though 91% reported actually having muscle spasms
Seventy-eight percent of the respondents proactively started a discussion with their clinician after developing symptoms of spasticity. However, 42% said they waited a year or longer after symptom onset to do so. Most said they wish they had talked with their clinician sooner. Survey participants added that clinicians used the term spasticity roughly two-thirds of the time when discussing the condition with them.
The study’s authors said that these results “emphasize that physicians and patients may benefit from use of a common language and underscore the importance of education, enabling earlier recognition, diagnosis, and treatment of spasticity in MS.”
Restless leg syndrome, or RLS, is much more common in people with MS than the general population. However, a recent study involving almost 200 people found that the condition did not adversely affect their mobility, their self-reported degree of disability, their mental or physical quality of life, or their employment status.12
That’s the good news. The not-so-good news is that the study participants with RLS had more impairment of their fine motor function than others with MS who do not have RLS. Further, they had a worse perception of their physical health than the people unaffected by RLS, and were more likely to report that their physical health imposed limitations on their ability to work or engage in other activities.
The study analyzed survey responses provided by 198 people with MS receiving care at Duke University Hospital in Durham, NC. Twenty percent of the participants reported having RLS.
Noting that earlier research has shown that up to one-third of people with MS who have RLS symptoms do not talk with their neurologists about those symptoms, the study’s authors concluded: “The impact of RLS on fine motor function and health perceptions suggests that patients with MS may benefit from being screened for RLS and offered treatment if symptoms are reported.”
A study of 1,052 people with relapsing MS and their clinicians found that healthcare professionals (HCPs) often do not recognize depression, fatigue, and other “hidden” symptoms that their patients are experiencing.13
The analysis drew on data from the Adelphi MS Disease Specific Program, an international survey of HCPs and their patients with MS. Both the clinician and the patient completed a form that included information on perceived MS severity, the presence of various symptoms, and MS management.
Clinicians and patients were largely aligned on the severity of MS. For instance, HCPs reported that 29% of patients had very mild MS, and 23% of patients assessed their MS as being very mild. However, while HCPs thought that only 2% of their patients had severe MS, 15% of patients deemed their multiple sclerosis as being severe.
Differences in clinician and patient perceptions were much more pronounced when it came to less-obvious symptoms. While HCPs reported that 24% of their patients felt low or were depressed, 67% of the people with MS reported those symptoms. Similarly, clinicians thought that only 10% of patients had difficulty concentrating, while 67% of patients reported this challenge. There also were notable mismatches in terms of mental fatigue (perceived by 31% of physicians and 45% of patients) and physical fatigue (42% vs. 54%)
The study’s authors concluded that their research “highlights the need for an all-inclusive conversation between the patient and the HCP that incorporates clinical and patient-relevant aspects of MS to optimize treatment and ensure that patient concerns and needs are being addressed.”
The relatives and other unpaid caregivers for people with MS carry a heavy burden and risk burnout, but they also experience a high degree of satisfaction with life, according to a recent study.14
Researchers surveyed 300 people who serve as the unpaid adult primary caregivers for an adult with MS. Eighty-two percent of the survey respondents were male, 86% were 35 years of age or older, and 96% were white. Almost half (48%) reported providing care to a spouse or former spouse, while 21% cared for a parent, and 14% tended to the needs of their child. The average duration of caregiving was 11.6 years. Ninety percent of the caregivers had paid jobs outside of their caregiving.
Eighty-one percent said that caregiving impaired their ability to work, and 75% reported that their regular activities were affected by caregiving. Given those findings, it’s not surprising that 82% had scores on the Caregiver Burden Inventory indicating that they had a high degree of burden and were at risk for burnout and that their average scores on the Hospital Anxiety and Depression Scale (HADS) reflected a moderate level of anxiety.
On the bright side, however, the mean depression score on the HADS instrument showed that most caregivers were not depressed, and average scores on the Satisfaction With Life Scale (SWLS) showed a high degree of satisfaction with life. In fact, 85% of study participants reported that their caregiving tasks “quite frequently” or “nearly always” made them feel useful or needed and 73% said that the work frequently or almost always gave them a sense of fulfillment.
A study of 500 people with MS found that 37% had alterations in their resting electrocardiograms (ECGs).15
Bradycardia, or a heart rate of less than 60 beats per minute (BPM), was the most common finding, and was documented in 33% of those with ECG alterations. Tachycardia, or a heart rate greater than 100 BPM, was the next most common finding, recorded in one-quarter of those with ECG alterations. Other findings included bundle branch blocks, which indicate a delay or blockage in the pathway that electrical impulses travel to generate a heartbeat, and ECG evidence of left atrial enlargement.
The study examined findings from resting ECG readings that had been verified by a cardiologist. ECGs were not included in the analysis if they had been recorded during an acute illness, trauma, allergic reaction, exacerbation of coronary artery disease, or stress testing. Similarly, ECGs performed to monitor people receiving initial treatment with an MS medication known to affect cardiac rate and rhythm were excluded, as were ECGs of patients taking other medications known to affect heart rate. The study subjects had an average age of 55.9 years. Three-quarters were female and 83% were white.
Now, before your heart skips a beat, some important context is in order. First, researchers have long known that having MS can be associated with alterations in ECG findings. This study sought to build on that existing knowledge by characterizing which alterations are seen in MS and how frequently they occur. Second, researchers are still exploring the extent to which these changes are directly related to MS versus being tied to the consequences of MS – such as a sedentary lifestyle – or entirely unrelated to MS, such as the natural effects of aging.
People with MS experience autonomic dysregulation, meaning altered functioning of their autonomic nervous system, which controls heart rate, respiratory rate, body temperature, and more. Autonomic dysregulation plays a role in the heat sensitivity that many people with MS experience, and may also contribute to the bradycardia and tachycardia reported in this study. Other aspects of heart function and overall cardiovascular health may not be directly related to MS itself but may reflect its consequences, such as not exercising. To the extent that heart health is affected by modifiable factors, such as diet and physical activity, people with MS have an opportunity to enhance their wellbeing.
While these findings are not cause to set your heart racing, or for you to race to the doctor’s office, they provide one more reason to talk with your MS clinician and other healthcare providers about your cardiovascular health, and to take the steps available to you to keep your heart beating steady and strong.
Forty percent of people newly diagnosed with MS are not sufficiently active and 34% are not active on a regular basis, according to a recent study.16
The research used a series of questionnaires to assess the degree of physical activity in 152 people who had received a diagnosis of MS in the past two years. Study investigators found that motivation and people’s sense of their own capability were key determinants of their degree of physical activity.
With a wealth of other studies documenting the physical and mental health benefits that people with MS derive from regular activity, this study provides one more reason to talk with your clinician about an exercise program appropriate for your particular situation and to get (or keep) moving.
1 Zehms J, Porwal MH, O’Dell S, et al. Epstein-Barr Virus, but not Herpes Simplex Viruses, is associated with multiple sclerosis. Int J MS Care. 2022; 24 (Supplement 1): 13.
2 Lock CB, Cohen JA, Lublin FD, et al. NurOwn (MSC-NTF) Phase 2 clinical trial in progressive MS: effects on cerebrospinal fluid inflammatory biomarkers. Int J MS Care. 2022; 24 (Supplement 1): NIB02.
3 National Library of Medicine. Safety and efficacy of repeated administration of NurOwn (MSF-NTF cells) in participants with progressive MS. ClinicalTrials.gov Identifier: NCT03799718. Clinicaltrials.gov. Accessed July 18, 2022.
4 Alvarez E, Steinman L, Fox EJ, et al. Reduced disease progression with ublituximab vs teriflunomide in the Phase 3 Ultimate I and II studies in relapsing multiple sclerosis. Int J MS Care. 2022; 24 (Supplement 1): DMT03.
5 TG Therapeutics. TG Therapeutics announces FDA extension of BLA PDUFA date for ublituximab to treat patients with RMS. Press release. May 31, 2022.
6 Montalban FX, Wolinsky JS, Arnold DL, et al. Safety and efficacy of evobrutinib, a Bruton tyrosine kinase inhibitor, in relapsing multiple sclerosis over 2.5 years of the open-label extension to a Phase 2 trial. Int J MS Care. 2022; 24 (Supplement 1): DMT02.
7 Cree BAC, Selmaj KW, Steinman L, et al. Long-term efficacy and safety, including COVID-19 outcomes, among ozanimod-treated patients with relapsing multiple sclerosis in the DAYBREAK open-label extension trial. Int J MS Care. 2022; 24 (Supplement 1): DMT14.
8 Di Bernardo A, Turkoz I, Kutch M, Ait-Tihyaty M. Ponesimod demonstrated increased clinical benefit over teriflunomide in an early disease subgroup compared with the overall population. Int J MS Care. 2022; 24 (Supplement 1): DMT09.
9 Blevins A, Turco E, Zuckerman AD, et al. Adherence to disease-modifying therapies in patients with multiple sclerosis across health system specialty pharmacies. Int J MS Care. 2022; 24 (Supplement 1): DMT27.
10 Hendin B, Thrower BW, Newsome SD, et al. Variability of spasticity in multiple sclerosis: results from SEEN-MSS, a large-scale, self-reported survey. Int J MS Care. 2022; 24 (Supplement 1): SYM01.
11 Hendin B, Thrower BW, Newsome SD, et al. Recognition and awareness of spasticity in multiple sclerosis: optimizing the patient/clinical dialogue – SEEN-MSS Survey. Int J MS Care. 2022; 24 (Supplement 1): DXM02.
12 Masha N, Gregory S, Giarraputo J, et al. Restless legs syndrome in individuals with multiple sclerosis: effects on disability and perceived physical health. Int J MS Care. 2022; 24 (Supplement 1): QOL18.
13 Le HH, Keenan A, Cole M, et al. Physicians and patients have different perspectives on burden of hidden symptoms of multiple sclerosis to patients. Int J MS Care. 2022; 24 (Supplement 1): MDC01.
14 Williams MJ, Totev TI, Obando C, et al. Understanding the burden of caring for patients with multiple sclerosis: A US caregiver survey. Int J MS Care. 2022; 24 (Supplement 1): MOC05.
15 Dhari Z, Paro A, Huselid R, et al. Prevalence and types of resting electrocardiography findings in persons with multiple sclerosis. Int J MS Care. 2022; 24 (Supplement 1): MDC07.
16 Huynh TLT, Motl RW. Physical activity behavior in persons newly diagnosed as having multiple sclerosis: patterns and correlates. Int J MS Care. 2022; 24 (Supplement 1): REH06.
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