What’s New in MS Research – November 2021

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

Two major meetings held last month showcased hundreds of studies addressing every aspect of multiple sclerosis (MS), from the efficacy and safety of investigational agents and the long-term impact of FDA-approved therapies, to MS risk factors and biomarkers of disease course. Symptom management, strategies for enhancing comprehensive care, and other practical components of managing MS were also featured prominently in the research unveiled at the annual meetings of the Consortium of Multiple Sclerosis Centers (CMSC) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

This month’s edition of “What’s New in MS Research” reports on a dozen of the studies presented at those meetings, including two poster presentations by the Multiple Sclerosis Association of America (MSAA).

More evidence on the benefits of starting DMTs sooner rather than later

People who started disease-modifying therapies (DMTs) soon after the onset of relapsing MS performed better on long-term measures of MS-related wellbeing than did those who began taking DMTs later in the course of their disease, according to a recent study.¹

Researchers drew on the Swedish MS Registry to study patient-reported outcomes in 2,484 people with MS who started a DMT within 2 years of disease onset and 203 people who began treatment with a DMT 2-4 years after MS onset. They matched people in the two groups by characteristics including age, sex, and Expanded Disability Status Scale score. The investigators then looked at scores from two surveys designed to measure patient-reported physical and psychological wellbeing to see how the study subjects fared in the 4-10 years following MS onset.

With an average follow-up period of 7.7 years, the people who began DMTs earlier had better scores for measures of MS-related physical health and psychological wellbeing than their counterparts who initiated therapy later. However, there were not significant differences between the two groups in general (versus MS-specific) health-related quality of life.

The study’s authors noted that these findings on patient-reported measures of MS-related health are consistent with evidence showing that people who start DMTs soon after diagnosis tend to have better long-term clinical outcomes than those who initiate therapy later.

Assessing the impact of Ocrevus^® on patients with early-stage relapsing-remitting MS

Eighty-six percent of people recently diagnosed with early-stage relapsing-remitting MS had no evidence of disease activity (NEDA) 48 weeks after beginning treatment with Ocrevus (ocrelizumab).² That finding emerged from the Phase IIIb ENSEMBLE study, which examined the impact of Ocrevus on measures including evidence of disease activity, annualized relapse rate (ARR), and disability progression.

Ocrevus is a monoclonal antibody – a laboratory-produced molecule that acts as a substitute for the body’s own antibodies, which play a key role in the immune system’s attack on harmful cells. The FDA has approved the medication, which is given by intravenous infusion, for use in adults with clinically isolated syndrome, relapsing-remitting MS, active secondary-progressive MS, and primary-progressive MS.

The ENSEMBLE study involved 1,225 patients. Sixty-four percent of the study subjects were female, and participants had a mean age of 32.7 years. Before treatment, their average Expanded Disability Status Scale (EDSS) score was 1.8, indicating a relatively low level of disability. Three-quarters of participants had experienced a relapse and also had magnetic resonance imaging (MRI) evidence of disease activity before starting treatment.

After 48 weeks of therapy, the participants’ average EDSS score improved from 1.8 to 1.67, indicating reduced disability. Their adjusted ARR was 0.042. This means that in a group of 100 people with MS, there would be roughly four relapses in the entire group over the course of 1 year. Investigators reported that the safety profile of Ocrevus® in ENSEMBLE was similar to that seen with the medication in other studies.

As clinicians work to individualize care to the greatest degree possible, data on specific types of MS patients – in this case recently diagnosed people with early-stage disease who had not received prior treatment for their MS – are critical to refining treatment strategies.

Investigational agent ublituximab lowers relapse rate in two Phase III studies

People with relapsing MS treated with the monoclonal antibody ublituximab had a 50% to 60% lower annualized relapse rate than study subjects receiving Aubagio® (teriflunomide) in the Phase III ULTIMATE I and ULTIMATE II trials.³

In ULTIMATE I and ULTIMATE II, more than 1,000 patients from 10 countries were assigned in random fashion to receive either ublituximab, administered via a 1-hour infusion every 24 weeks, or 14 mg of Aubagio, taken orally each day, for 96 weeks. The primary endpoint of both studies was the annualized relapse rate, or ARR.

In ULTIMATE I, patients treated with ublituximab had an ARR of 0.076, compared to 0.1888 for Aubagio, a relative reduction of roughly 60% that was statistically significant. In ULTIMATE II, patients in the ublituximab group had an ARR of 0.091, versus 0.178 for the Aubagio group, a difference of about 50% that also was statistically significant.⁴

The rate of adverse events among people receiving ublituximab was similar to that of people treated with Aubagio. Approximately 88% of people in both groups had at least one adverse effect. The most common adverse events among people receiving ublituximab were infusion-related reactions, which were seen in 47.7% of people receiving the monoclonal antibody.

In October, TG Therapeutics, the developer of ublituximab, submitted an application to the United States Food and Drug Administration (FDA) seeking approval for use of the monoclonal antibody in relapsing forms of MS.

Study details tolebrutinib efficacy, safety profile over 48 weeks

Tolebrutinib is an investigational medication that inhibits an enzyme called Bruton’s tyrosine kinase, or BTK. The enzyme affects the B cells and microglial cells believed to play a role in the development of MS, and researchers hope to modulate the neuroinflammation of MS through inhibiting BTK and, thus, targeting those immune system cells.

After a 12-week Phase II study of tolebrutinib showed encouraging results, researchers invited study participants to enroll in a longer trial that examined the efficacy and safety profile of the oral medication over a longer period. One hundred and twenty-two patients were studied through 48 weeks. In the first part of the extended study, participants remained on the dose of tolebrutinib they had received initially – either 5 mg, 15 mg, 30 mg, or 60 mg per day. In the second part of the study, all participants received 60 mg per day, which is the dose being studied in the ongoing Phase III GEMINI 1 and GEMINI 2 trials.^{5, 6}

At Week 48, the mean number of new gadolinium-enhancing lesions seen on magnetic resonance imaging (MRI) remained low (<0.4) in people who had been on 60 mg of tolebrutinib since the initial study. Meanwhile, people who had been on lower doses of the medication initially and then switched to 60 mg during the second part of the extension study had a reduction in the number of gadolinium-enhancing lesions.

The annualized relapse rate in people receiving 60 mg of tolebrutinib was 0.17, with 89.5% of patients having no relapses during the study period.

No new safety signals emerged during the 48-week study. The most frequent adverse events were headache (10%), COVID-19 (9%), upper respiratory tract infection (8%), and nasopharyngitis (7%).

The GEMINI I and II Phase III studies of tolebrutinib are expected to be completed in 2023.⁷

Examining how prior use of different DMTs affects stem cell treatment outcomes

People with MS who undergo stem cell treatment usually do so because they have not had a satisfactory response to a disease-modifying therapy (DMT). Does which DMT you took in the 6 months prior to stem cell treatment have an impact on how well stem cell therapy works? A recent study involving 104 patients from Sweden and Norway examined that question.⁸

All 104 people had relapsing forms of MS. They received stem cells that were taken from their own blood-cell-forming tissues, treated, and then reinfused into their bodies. Seventy-nine of the study subjects had taken a DMT in the 6 months prior to stem cell therapy. Researchers followed the people over an average of 39.5 months.

Eighty-four of the individuals had no evidence of disease activity (NEDA) after stem cell therapy, while the other 20 had post-treatment disease activity. The people with no evidence of disease activity included all of the patients who previously had received Lemtrada® (alemtuzumab), Aubagio® (teriflunomide), Mavenclad® (cladribine), or Rituxan® (rituximab). Please note that Rituxan is approved in the United States for the treatment of several cancers and autoimmune conditions, but not for the treatment of MS; however, it is sometimes used “off-label” in certain circumstances for individuals with MS.

By comparison, 50% of patients who had received an interferon-based DMT had new disease activity following stem cell treatment, as did 33% of those who had received prior Gilenya® (fingolimod), 25% of those who had taken Copaxone® (glatiramer acetate), and 20% of those who had received Tysabri® (natalizumab) or Tecfidera® (dimethyl fumarate).

The incidence of developing neutropenic fever – a common complication of stem cell treatment – and the length of hospitalization following receipt of stem cells did not vary based on which DMT a patient had received previously.

When steroids don’t quell relapses: Evaluating repository corticotropin injection

Researchers estimate that 20% to 35% of acute MS relapses don’t respond to high-dose corticosteroids. One option in such cases is daily injections of repository corticotropin, a hormonally based treatment approved by the FDA.

Repository corticotropin injection (RCI) was previously referred to as “ACTH Gel.” It has been used as an alternative to corticosteroids for more than 30 years and contains a highly purified form of the hormone adrenocorticotropin (ACTH) in gelatin. It is given once daily for two-to-three weeks and is injected either into the muscle or under the skin. The corticotropin is absorbed slowly into the bloodstream and works differently than corticosteroids by helping the body to produce its own natural steroid hormones that reduce inflammation and aid in recovery.

Investigators recently assessed the efficacy and safety of RCI in 35 relapsing-remitting MS patients whose relapses had not responded to intravenous or oral methylprednisolone, or to oral prednisone.⁹ Seventy-seven percent of the patients were women, and 86% were Caucasian. Study participants were randomized to receive daily injections of 1 mL of RCI or placebo for 14 days. The study’s primary efficacy endpoint was Expanded Disability Status Scale (EDSS) response rate at Day 42, which was defined as the percentage of patients with an EDSS-score improvement of 1 point or more if their baseline EDSS score was 5.5 or less, and of 0.5 points if their initial EDSS score was more than 5.5.

At Day 42, 61% of the RCI recipients had an improvement in the EDSS score, compared to 11% of people in the placebo group. Meanwhile, the incidence of treatment-emergent adverse events was 77.8% for those in the RCI group versus 70.6% in the placebo group. There were no serious adverse events or deaths in the RCI group.

The study’s investigators concluded, “These results support RCI as a safe and highly effective treatment for MS relapse in patients with an inadequate response to high-dose corticosteroids.”

Assessing the “whole-person” impact of spasticity on people with MS

The pain and mobility limitations of spasticity create very real and obvious challenges, but they are far from the only ways the musculoskeletal condition negatively affects people with MS, a recent study found.¹⁰

Researchers employed an online survey to ask 961 adults with MS about the impact spasticity had on their lives. All survey participants lived in the United States. Their mean age was 56.6 years, and 78% were female.

Ninety-three percent reported experiencing pain due to spasticity, and 92% said the condition limited them in performing daily activities, including walking, climbing stairs, and various household activities. Eighty-nine percent said spasticity impaired their ability to sleep. Seventy-two percent of respondents said spasticity was among the most problematic symptoms of their MS.

While those findings might not be surprising, the survey also detailed the extent to which spasticity has an impact on people’s emotional health and sense of self, including:

• Negative impact on emotional wellbeing – 88% of respondents
• Reduced sense of self-confidence – 75%
• Negative impact of self-image – 71%
• Sense of dependence on others – 62%
• Feeling isolated – 40%

Further, 39% said they had a fear of falling due to their spasticity, while 35% said it impaired their ability to relax, and 27% said it contributed to a sense of helplessness.

While clinicians long have appreciated and sought to address the physical ramifications of MS-related spasticity, these findings underscore the importance of clinicians and patients alike discussing and managing the full range of issues that spasticity can cause, with the goal of enhancing overall quality of life.

Restless leg syndrome may be tied to MS-lesion location and degree of disability

Restless leg syndrome (RLS) is as common in multiple sclerosis as it is aggravating, with up to 60% of people with MS thought to experience the lower-limb twitches and troubles that mark the condition.

Now, Turkish researchers have found indications that RLS may be linked to the presence of spinal cord lesions and a relatively greater degree of MS disability.¹¹ They base those conclusions on a study of 959 people with MS. Of that group, 222 of the study subjects also met the clinical criteria for RLS. A review of MRI scans by three neurologists who did not know which patients had or had not been diagnosed with RLS, found that people with one or more lesions on their cervical spinal cord were 1.5 times more likely than others to have restless legs. Having lesions on the brainstem or thoracic spinal cord was not associated with increased risk for RLS.

Meanwhile, in interviewing patients and reviewing their medical records, the researchers found no association between age, sex, body mass index, or disease duration and risk of RLS. They did, however, find that people with RLS were likely to have a higher degree of disability than other people with MS. Recognizing that association can be helpful to clinicians and patients alike as they develop comprehensive plans to manage MS and its frequently accompanying conditions.

New support for the Mediterranean/MIND diet in MS

A new study of 400 adults with MS found that those who followed a Mediterranean diet (MeDi) or the MeDi-DASH Intervention for Neurodegenerative Delay (MIND) diet performed better on an assessment of MS function than their counterparts with other eating habits.¹²

While there is no hard-and-fast definition of the Mediterranean diet, it is generally considered to consist of fruits, vegetables, whole grains, nuts, seeds, and heart-healthy fats, while limiting processed foods, added sugar, and refined grains. Meanwhile, the MIND eating plan combines the Mediterranean diet with elements of the Dietary Approaches to Stop Hypertension (DASH) diet in an effort to delay neurodegeneration. The DASH diet focuses on consumption of berries and reduced sodium intake, among other features.

Study participants had an average age of 43.9 years. Two hundred and eighty-one of the participants were women and 67 had a progressive form of MS. They filled out a survey on their dietary habits and also completed the MS Functional Composite (MSFC) questionnaire, as well as other assessments.

After making adjustments for factors such as race, ethnicity, smoking, and socioeconomic status, researchers found that the more people’s eating habits were in line with the MeDi or MIND diets, the more likely they were to have MSFC scores that reflect better functioning. The investigators also noted indications that the link between diet and function was stronger in the setting of progressive MS than in relapsing-remitting MS.

Exploring the movement-mood connection in people with MS

It’s hard to get moving when you’re feeling down. But recent research suggests that activity might be just the ticket (or at least part of the solution) for people with MS who are seeking to elevate their mood.

Investigators asked 640 people enrolled in the iConquerMS research initiative to provide information about the frequency and nature of their physical activity and to complete the Neuro-QoL survey, which assesses mood, cognitive function, and other aspects of quality of life. Ninety-one percent of participants were non-Hispanic White. Eighty-five percent were female, and 65% had relapsing-remitting MS. The remainder had other forms of MS. Their average age was 52 years.

The researchers found that participants who were less likely to exercise were more likely to report increased symptoms of depression.¹³ This correlation held true regardless of participants’ degree of disability. Study authors said their research suggested that the impact of exercise on patient-reported outcomes should be considered when designing physical activity interventions for people with MS.

Posters Presented by MSAA

App empowers people with MS to track, discuss, and manage their symptoms

If knowledge is power, a complementary app developed by the Multiple Sclerosis Association of America (MSAA) and @Point of Care provides a particularly powerful way for people with MS to deal with commonly experienced symptoms that can have a major impact on quality of life.

My MS Manager™ is a HIPAA-compliant app that people can download at no charge from the Apple App Store, the Google Play Store, or at https://mymsaa.org/msaa-community/mobile/. The app enables users to track disease activity, store medical information in a secure setting, and generate charts and reports across various metrics, such as treatments, moods, symptoms, and more.

A recent analysis evaluated data from more than 7,400 people with MS who are using the app. More than 4,600 of those people identified themselves as having relapsing-remitting MS, while 658 said they have secondary-progressive multiple sclerosis (SPMS) and 455 have primary-progressive MS (PPMS).¹⁴

In assessing aggregate data de-identified to ensure the anonymity of all respondents, the analysis found that users with SPMS reported significantly more bladder control issues and significantly greater depression than those with RRMS. For example, 36% of users with SPMS said they are having increased bladder accidents vs. 18% of people with RRMS. Similarly, 16% of people with SPMS and 7% of those with RRMS said bladder issues have severely affected their lifestyle. The differences between groups with regard to frequency of accidents and impact on lifestyle both were statistically significant.

Interestingly, people with RRMS who were infrequent users of My MS Manager™ – defined as those with 28 or fewer visits to the app – reported higher levels of several negative aspects of MS compared to more-frequent app users. Specifically, they had higher self-reported levels of depression severity, sleep issues, problems concentrating, lack of energy, feelings of hopelessness, and difficulty doing their work, among other issues.

The authors of the analysis noted that the patient app enables people with MS to “record their symptoms using validated measures and empowers them to track, manage, and discuss their symptoms with their clinicians.”

Bridging gaps between managed care executives and MS clinicians to enhance care

The comprehensive care of people with MS requires a comprehensive approach, one in which everyone with a role to play is aligned on the overall objective. Often, however, people pursuing the same goal can speak slightly different languages, potentially leading to misunderstandings.

To avoid such “bumps in the road” on the path to delivering high quality MS care, the Multiple Sclerosis Association of America (MSAA) recently joined with Impact Education and Medical Education Resources to facilitate in-depth roundtable discussions between managed care decision-makers and MS clinicians.¹⁵ The discussions took place at four roundtables held from August 2019 through January 2020 in Los Angeles, Chicago, Atlanta, and the Washington, DC area. The activity was supported by educational donations from Biogen, Celgene Corporation, and Genentech, Inc.

More than two dozen people participated in the roundtables, including MS center medical directors, academic medical center neurologists and other specialists, pharmacy directors, managed care executives, and advocacy organization leaders. These experts identified priorities such as enhancing the patient experience, delivering high-quality care, improving healthcare affordability, and improving access to appropriate care.

Key take-aways for providers participating in the collaborative process included further evaluating outcomes, increasing multidisciplinary care, and identifying specific barriers to improving processes. Among participants from managed care, the key take-aways included providing for continuity of care when patients are experiencing good results on an established therapy, exploring care-management programs for people with MS, and greater engagement with specialty pharmacies in terms of sharing action-driving data.

The discussion process already has yielded a white paper titled “The Evolving Landscape in the Management & Treatment of Multiple Sclerosis: Payer Considerations for Providing Support to People with MS and Their Care Partners.” Future steps may include the formation of a Steering Committee through MSAA, forging consensus on outcomes, and further efforts to share data and continue the dialogue.

---

Please note that MSAA will publish additional information from the CMSC and ECTRIMS annual meetings in the January 2022 edition of “What’s New in MS Research.”

---

References

¹ He A, Hillert J, Spelman T, Ciccarelli O, McKay K. Earlier disease modifying therapy is associated with more favourable long-term patient reported outcomes in relapsing multiple sclerosis. Poster P233. ECTRIMS 2021.

² Hartung H-P, Bermel R, Freedman MS, et al. Recently diagnosed early-stage RRMS: NEDA, ARR, disability progression, serum neurofilament and safety: full cohort 1-year data from the ocrelizumab Phase IIIb ENSEMBLE study. Poster P628. ECTRIMS 2021.

³ Steinman L, Fox EJ, Hartung H-P, et al. Efficacy and safety of ublituximab versus teriflunomide in relapsing multiple sclerosis: results of the Phase 3 ULTIMATE I and II trials. Abstract DMT04. CMSC 2021.

⁴ TG Therapeutics. TG Therapeutics announces data for ublituximab in multiple sclerosis presented at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis. October 14, 2021. Available at: https://www.globenewswire.com/news-release/2021/10/14/2314474/8790/en/TG-Therapeutics-Announces-Data-for-Ublituximab-in-Multiple-Sclerosis-Presented-at-the-37th-Congress-of-the-European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis.html. Accessed November 1, 2021.

⁵ Oh J, Syed S, Orogun L, et al. Safety and efficacy outcomes from the long-term extension study of tolebrutinib in patients with relapsing MS: Year 1 results. Poster P667. ECTRIMS 2021.

⁶ Sanofi. New long-term data reinforcing promising safety and efficacy profile of brain-penetrant tolebrutinib presented at ECTRIMS 2021. October 13, 2021. Available at https://www.sanofi.com/en/media-room/press-releases/2021/2021-10-13-09-00-00-2313117. Accessed November 2, 2021.

⁷ clinicaltrials.gov

⁸ Kvistad S, Burman J, Bo L, et al. The impact of previous disease-modifying treatment for HSCT outcome and the risk of new disease activity in MS. Poster P952. ECTRIMS 2021.

⁹ Miller A, Goldstick L, Bauer W, et al. Results from a multicentre, randomised, double blind, placebo-controlled study of repository corticotropin injection for multiple sclerosis relapse that inadequately responded to corticosteroids. Poster P107. ECTRIMS 2021.

¹⁰ Newsome SD, Thrower B, Hendin B, et al. Beyond the physical symptoms of spasticity for persons with multiple sclerosis spasticity. Results from the SEEN-MSS, a large-scale, self-reported survey. Abstract REH07. CMSC 2021.

¹¹ Ozakbas S, Ozdogar AT, Baba C, et al. Relationship between presence of spinal cord lesion and restless legs syndrome in multiple sclerosis. Poster P97. ECTRIMS 2021.

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

¹³ Tyszka EE, Briggs FSS. Characterizing the relationship between neurological/mental health and physical activity levels in persons with multiple sclerosis. Abstract REH20. CMSC 2021.

¹⁴ Rudell E, Agrawal T, Peterson P, Griffin AL, Ingram M, Bowen J. Empowering patients through technology to manage and track symptoms of MS. Poster QOL16. CMSC 2021.

¹⁵ Pinion K, Crispino A. The evolving landscape in the management & treatment of multiple sclerosis: payer considerations for providing support to people with MS and their care partners.” CMSC 2021.

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