What’s New in MS Research – September 2021
Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD
Asking questions is the engine that drives progress in multiple sclerosis (MS) care globally and individually.
Whether it’s a researcher inquiring into the safety and effectiveness of an investigational therapy, a clinician posing a question that will help shape a treatment strategy, or a person with MS seeking guidance on how best to manage a symptom, finding the right answer depends on asking the right question.
This edition of “What’s New in MS Research” contains an array of hopeful, reassuring, and intriguing answers to important questions about living with multiple sclerosis.
Those answers take the form of results from a Phase II study of a potential new MS therapy, tolebrutinib, as well as findings from a long-term study of a well-established disease-modifying therapy, Tecfidera® (dimethyl fumarate). They include other findings that address questions ranging from whether vaccination against COVID-19 increases relapse risk and how sexual and gender minority (SGM) individuals assess their MS care, to what characteristics are indicative of quality care and whether horseback riding can improve balance and mobility in MS. Other items focus on questions still to be answered, including whether people with MS should receive COVID-19 boosters and whether a new approach to stem cell therapy can improve symptoms in mild-to-moderate MS.
We hope these items will provide insights into some of your questions. We also hope you will continue to turn to the Multiple Sclerosis Association of America (MSAA) whenever you have questions related to MS. Please review the resources available on our website at mymsaa.org.
Findings from a Phase II study of the investigational medication tolebrutinib support conducting Phase III trials to further evaluate its efficacy and safety in people with relapsing-remitting multiple sclerosis (RRMS), researchers said.1
Tolebrutinib inhibits Bruton’s tyrosine kinase, or BTK. BTK is an enzyme expressed in B cells and myeloid cells, which are components of the body’s innate immune system, and in microglia, which are innate immune cells in the central nervous system. B cells, myeloid cells, and microglia all are believed to play a role in the inflammation seen in MS.
The Phase II study involved 130 people ages 18 to 55 years who had been diagnosed with RRMS. The research examined how four different doses of tolebrutinib affected the number of new gadolinium-enhancing lesions seen on magnetic resonance imaging (MRI) after 12 weeks of treatment with the oral medication. Researchers compared the number of new lesions seen at Week 12 with the number identified earlier in the course of treatment and with the number that accumulated during the four weeks when one group of study participants received placebo before beginning tolebrutinib.
The investigators found a dose-dependent reduction in the number of new lesions seen per patient. For example, while there were an average 1.03 new lesions in the placebo group, that number dropped to 0.77 for those receiving 15 mg of tolebrutinib daily and to 0.13 for those taking the highest dose – 60 mg – of tolebrutinib each day. (The other doses studied were 5 mg and 30 mg daily.)
One serious adverse event was reported. It involved a patient in the 60-mg tolebrutinib group being admitted to the hospital for an MS relapse. Researchers said that the most common non-serious adverse event occurring during tolebrutinib treatment was headache, which affected 3% of those in the 5-mg group, 9% in the 15-mg group, 3% in the 30-mg group, and 13% of those receiving 60 mg of tolebrutinib. Investigators added that there were no safety-related study discontinuations or treatment-related deaths.
The United States Food and Drug Administration (FDA) has authorized Hope Biosciences Stem Cell Research Foundation (HBSCRF) to conduct a Phase II trial examining the efficacy and safety of infusing a patient’s own stem cells to improve symptoms and quality of life in people with mild-to-moderate MS, the non-profit foundation reported.2
The randomized, double-blind trial will involve 24 patients, who will receive six intravenous infusions of adult stem cells, harvested from their own fat tissue, over 32 weeks. A single infusion given to people randomly assigned to the treatment group will consist of 200 million stem cells, so that those patients each will receive approximately 1.2 billion stem cells over the course of study, the Foundation noted.
“While this is our first study for multiple sclerosis, our focus has been on chronic neurodegenerative diseases for some time,” explained Donna Chang, founder of HBSCRF. “We hypothesize that the stem cells, given in high, repeated doses, will be able to regulate the immune system so that the body stops attacking itself. Degeneration must stop in order for regeneration to be possible.”
The Foundation reported that it has obtained FDA authorization for 22 clinical studies in 12 disease areas, including COVID-19 prevention and treatment, traumatic brain injury, and Parkinson’s disease, as well as multiple sclerosis. Launched in March 2020, HBSCRF administered nearly 100 billion cells at no charge to patients in its first year of operation.
A study that monitored use of Tecfidera (dimethyl fumarate) for up to 13 years in people with relapsing-remitting multiple sclerosis (RRMS) found that the disease-modifying therapy (DMT) provided ongoing efficacy and maintained a consistent safety profile, researchers said.3
The ENDORSE trial involved more than 1,700 people with RRMS, including many who also had participated in the Phase III DEFINE and CONFIRM trials of Tecfidera. The median follow-up period was 8.76 years, with 52% of those treated in ENDORSE followed for more than six years. Study participants included some who had received placebo (PBO) for up to two years before switching over to Tecfidera (DMF) for up to 10 years. These people constituted the PBO/DMF group. Other study participants received Tecfidera the entire time. They made up the DMF/DMF group.
The overall annualized relapse rate (ARR) in the DMF/DMF group was 0.143, while the overall ARR for those who had received placebo before Tecfidera was 0.151. Meanwhile, over 10 years, 72% of people in the DMF/DMF group and 73% of those in the PBO/DMF group had no 24-week confirmed disability worsening.
Thirty-two percent of patients experienced serious adverse events during the follow-up period. Relapses and falls were among the most common adverse events, although there was one case of progressive multifocal leukoencephalopathy, as well as some rare opportunistic infections, malignancies, and serious herpes zoster infections. Fourteen percent of people discontinued treatment due to adverse events, with gastrointestinal disorders being common reasons cited for stopping therapy.
Assessing the results, study investigators concluded that the findings supported a positive benefit/risk profile for Tecfidera for long-term treatment of RRMS.
An Italian study of 324 people with MS who received the Pfizer/BioNTech COVID-19 vaccine found no increased risk of clinical relapse in the first two months after vaccination.4
Six of the people studied had clinical relapses in the two months before their first vaccination, while seven had clinical relapses in the two months following vaccination. The one-person difference in pre- and post-vaccination relapses was statistically insignificant, researchers noted.
The average age of study participants was 42.7 years. Three-quarters of people in the study were female, and 92% were taking a disease-modifying therapy (DMT) at the time of vaccination. Investigators reported that demographic characteristics, such as age and gender, and disease characteristics, such as time since diagnosis and Expanded Disability State Scale score, did not affect risk of relapse.
Among the seven people who experienced a relapse after vaccination, the average time between receiving the first dose of the Pfizer/BioNTech vaccine and relapse was 44 days. Six of the seven people who had post-vaccination relapses were taking a DMT.
The study’s authors noted that well before the COVID-19 pandemic, clinicians and patients alike often debated the potential impact of various vaccines on MS. Their findings, they added, support the recommendation of several medical societies and MS patient advocacy groups that people with MS should be vaccinated against COVID-19.
The National Institutes of Health (NIH) has begun a clinical trial to assess the antibody response to an extra dose of COVID-19 vaccine in people with multiple sclerosis (MS) or other autoimmune disease who did not respond to an original COVID-19 vaccine regimen. 5The Phase II trial is sponsored and funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).
“Many people who have an autoimmune disease that requires immunosuppressive therapy have had a poor immune response to the authorized and approved COVID-19 vaccines, placing these individuals at high risk for the disease,” said NIAID Director Anthony S. Fauci, MD. “We are determined to find ways to elicit a protective immune response to the vaccines in this population. This new study is an important step in that direction.”
The NIH trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, initially will include people with one of five autoimmune diseases: multiple sclerosis; pemphigus (painful autoimmune disease causing blisters and sores); rheumatoid arthritis; systemic lupus erythematosus; or systemic sclerosis (also known as scleroderma).
The study team will enroll approximately 600 participants ages 18 years and older at 15 to 20 sites nationwide. Participants must have had a negative or suboptimal antibody response to two doses of the Moderna COVID-19 vaccine, two doses of the Pfizer-BioNTech COVID-19 vaccine, or one dose of the Johnson & Johnson’s Janssen COVID-19 vaccine. Participants also must be taking one of three immunosuppressive therapies: mycophenolate mofetil (MMF) or mycophenolic acid (MPA); methotrexate (MTX); or B cell-depleting drugs. Of those three immunosuppressive therapies, only B cell-depleting drugs are approved by the FDA for use in MS.
All participants will receive an extra dose of the COVID-19 vaccine they received originally. Then those participants who are taking MMF/MPA or MTX will be assigned at random either to continue taking their immunosuppressive medication without alteration or to pause taking their medication for a short period before and after receiving the extra vaccine dose. This medication pause will not apply to people with MS taking B cell-depleting therapies.
The main goal of the study is to determine the proportion of participants who have a significantly better antibody response four weeks after receiving the extra vaccine dose than they did after their original vaccinations. Study participants will be followed for 13 months. Preliminary results are expected in November.
Additional information about the COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders trial, including the locations of study sites, is available at ClinicalTrials.gov under study identifier NCT05000216. This study information can also be found by visiting mymsaa.org/clinicaltrials and accessing the clinical trial Match tool.
Do the immunosuppressive effects of disease-modifying therapies (DMTs) taken by people with MS put those people at an elevated risk for worse outcomes from COVID-19? It’s a question that has concerned clinicians and patients alike since the pandemic began almost two years ago.
Now, two teams of researchers – one in Texas and one in Spain – have provided reassuring findings in separate studies.
The Texans identified 843 people with MS who had been diagnosed with COVID-19. They matched each of those people with two other people with similar demographic characteristics – such as age, sex, and other health conditions – who also contracted COVID-19 but who did not have MS.6 Among the study subjects with MS, researchers had information on DMT use in 332 patients. (Investigators explained that many more of the people with MS likely take DMTs, but that the electronic database they analyzed did not contain this information for many people.)
The study defined a severe COVID-19 outcome as one or more of the following: admission to an intensive care unit (ICU), mechanical ventilation, or death. Researchers found that patients who could not walk on their own – for whatever reason, not necessarily MS – and those with pre-existing conditions other than MS were at the highest risk for a severe COVID outcome. DMT use was not identified as a risk factor and, in fact, the authors wrote, “The majority of MS patients actively treated with a disease-modifying therapy (DMT) had mild disease.”
Meanwhile, the Spanish investigators analyzed records for 326 people with MS who had laboratory-confirmed or suspected COVID-19. Sixty-nine of those patients (21%) developed a severe infection, 10 (3%) were critically ill with COVID, and seven (2%) died.7
The researchers found that, “severe and critical infections were more likely to affect older males with comorbidities, with progressive MS forms, a longer disease course and higher disability.” They concluded: “The study has not demonstrated the presumed critical role of MS therapy in the course of COVID-19.”
How do you measure the quality of the MS care you receive? By your clinician’s willingness to take the time needed to answer your questions? Or perhaps by the thoroughness of the history and physical examination conducted at regularly scheduled visits, or by how quickly and easily you can reach your clinician when an issue arises?
While each person with MS tends to apply his or her own yardstick, two German researchers are working to identify a uniform set of criteria that can be used to assess and improve the MS care process.8
After vetting 465 papers and considering 226 quality indicators, they identified the following characteristics as being key:
- Having a process in place for people being treated for MS to report new or worsening symptoms;
- Promoting appropriate physical exercise;
- Taking a coordinated, multidisciplinary approach to care;
- Fostering active cooperation between the clinician and patient in the treatment decision-making process; and
- Offering treatment with disease-modifying therapies (DMTs) early in the disease process.
The researchers added that, “New sets of indicators must be tested and evaluated in the real-life setting to show the possibility of generating a positive impact for the people with MS.”
A majority of 26 sexual and gender minority (SGM) individuals participating in a recent survey reported satisfaction with their MS care, but 30% said they were uncomfortable discussing their sexual and/or gender identities with their clinician.9
The survey respondents, who live in northern California, had a mean age of 50.2 years. Forty-six percent identified as women, 38% as men, and 15% as genderqueer, transgender, or other. The participants’ self-reported sexual orientations were: gay/lesbian/bisexual, 35%; pansexual/queer, 27%; questioning 23%; and other identity, 15.%.
Seventy-nine percent of survey participants said they were somewhat or extremely satisfied with their MS care. Those who reported dissatisfaction with their care said they felt dismissed. More than 87% of respondents said they felt that their SGM identities did not affect their MS care.
Overall, the participants reported that MS had a low impact on their participation in SGM communities. Those respondents who said MS had a greater impact in this regard cited fatigue, immobility, and stigmatization of disease as key factors. Survey respondents also reported that SGM status had a low effect on their participation in MS communities. Those who noted a higher impact said that apprehension about identity disclosure to new groups of people was a factor.
The study’s authors noted, “Identified resources that might improve MS care included greater representation, inclusivity and openness from clinicians, and SGM-focused MS support groups.”
One in seven people with MS participating in a recent study reported some degree of bowel dysfunction, underscoring the importance of clinicians’ asking – and patients’ telling – about this key aspect of health and quality of life.10
Researchers at nine MS centers in Italy screened more than 1,100 people receiving outpatient care. Fourteen percent of those patients had moderate or severe bowel dysfunction, as signified by a score of 10 or greater on an instrument used to assess bowel dysfunction arising from neurologic causes.
Moderate to severe bowel dysfunction was seen more frequently in patients with:
- progressive – as opposed to relapsing – forms of MS;
- higher scores on the Expanded Disability Status Scale, indicating greater disability;
- older age;
- and/or longer disease duration.
Female sex, difficulty walking, and bladder symptoms were predictors of severe neurogenic bowel dysfunction.
Riding high – literally, on the back of a horse – may be an effective way to improve the balance issues, mobility problems, and fatigue that can lead to a lower quality of life for people with relapsing-remitting multiple sclerosis (RRMS).
That’s the conclusion of a study involving 33 people with RRMS.11 Seventeen of the study subjects were assigned to participate in 16 sessions of hippotherapy, the medical term for therapeutic horseback riding. The other 16 study subjects served as controls, continuing with whatever other therapeutic interventions they already had in place.
Researchers obtained baseline and end-of-study values for all participants on measures including center of pressure (CoP) assessments for balance, the Timed Up and Go (TUG) test for functional mobility, the Fatigue Severity Scale (FSS), and Modified Fatigue Impact Scale (MFIS) for fatigue, and the Functional Assessment of Multiple Sclerosis (FAMS) for quality of life.
After analyzing the data from those measures, investigators concluded that, “hippotherapy improved postural balance, functional mobility, fatigue, and quality of life in people with relapsing-remitting MS.” They added, “This suggests that hippotherapy may be a useful approach for complimentary treatment among people with MS.”
1. Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2021.20(9):729-738.
2. Hope Biosciences Stem Cell Research Foundation. FDA gives green light for multiple sclerosis stem cell trial. July 27, 2021. Available at https://www.businesswire.com/news/home/20210727005234/en/FDA-Gives-Green-Light-for-Multiple-Sclerosis-Stem-Cell-Trial. Accessed September 1, 2021.
3. Gold R, Arnold DL, Bar-Or A, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: final ENDORSE study results. Mult Scler. 2021 Sep 1;13524585211037909. doi: 10.1177/13524585211037909.
4. DiFilippo M, Cordioli C, Malucchi S, et al. mRNA COVID-19 vaccines do not increase the short-term risk of clinical relapses in multiple sclerosis. J Neurol Neurosurg Psychiatry. Epub ahead of print. Doi:10.1136/jnnp-2021-327200.
5. National Institutes of Health. NIH launches study of extra COVID-19 vaccine dose in people with autoimmune disease. August 27, 2021. Available at https://www.nih.gov/news-events/news-releases/nih-launches-study-extra-covid-19-vaccine-dose-people-autoimmune-disease. Accessed September 1, 2021.
6. Perez CA, Zhang G-Q, Li X, et al. COVID-19 severity and outcome in multiple sclerosis: results of a national, registry-based, matched cohort study. Mult Scler Relat Disord. 2021 Aug 16;55:103217.doi: 10.1016/j.msard.2021.103217.
7. Arrambide G, Llaneza-Gonzalex MA, Coasta-Frossard Franca L, et al. SARS-CoV-2 infection in multiple sclerosis: Results of the Spanish Neurology Society Registry. Neurol Neuroimmunol Neuroinflamm. 2021;8:e1024.
8. Kraft AK, Berger K. Quality of care for patients with multiple sclerosis – a review of existing quality indicators. Front Neurol. 2021. Aug 5;12:708723. doi: 10.3389/fneur.2021.708723.
9. Anderson S, Dierkhising J, Rush G, et al. Experiences of sexual and gender minority people living with multiple sclerosis in northern California: an exploratory study. Mult Scler Relat Disord 2021; Aug 14;55:103214.doi: 10.1016/j.msard.2021.103214.
10. Alvino B, Arianna F, Assunta B, et al. Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: an Italian multicenter study. J Neurol. 2021.https://doi.org/10.1007/s00415-021-10737-w.
11. Gomes Moraes A, Neri SGR, Motl RW, et al. Effects of hippotherapy on postural balance, functional mobility, self-perceived fatigue, and quality of life in people with relapsing-remitting multiple sclerosis: secondary results of an exploratory clinical trial. Mult Scler Relat Disord. 2021 Jul;52:102948.doi: 10.1016/j.msard.2021.102948.
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