What’s New in MS Research – January 2024

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

This edition of “What’s New in MS Research” highlights several of those findings. They include information on a telehealth program that drove significant weight loss in people contending with both MS and obesity, and an internet-delivered cognitive behavioral therapy intervention designed specifically for people with MS that has been shown to reduce depressive symptoms.

Other items include the reassuring long-term efficacy and safety information on Kesimpta^® (ofatumumab), a disease-modifying therapy approved in 2020 for use in relapsing forms of MS, as well as the Food and Drug Administration’s (FDA) provision of Fast Track designation for a cell therapy being evaluated for treatment of people with progressive forms of MS who have not had a satisfactory response to currently available therapies. While the items featured in this edition vary widely in terms of the specific aspects of multiple sclerosis that they address, they all speak to the progress being made in understanding and managing MS.

An effective approach to weight loss in people with MS and obesity

Two-thirds of people with MS and obesity who participated in a group-based telehealth program lost 5% or more of their body weight over six months.¹

Those impressive results emerged from the Modifying Diet and Exercise in Multiple Sclerosis (MoDEMS) trial, which enrolled 71 people with MS. Half of those people were assigned at random to participate in a telehealth program that provided guidelines for calorie reduction and increased physical activity. The other half were assigned to treatment as usual, serving as a control group.

After six months, people in the telehealth group had lost an average of 8.6% of their body weight, while those in the control group had lost 0.7% of their body weight. Beyond those averages, 65% of people in the telehealth group achieved what researchers considered meaningful weight loss, defined as reducing their body weight by 5% or more.

Further, people in the telehealth group engaged in 46.2 more minutes per week of moderate-to-vigorous physical activity than their control group counterparts and showed improved quality of life on standardized assessments. Weight loss also was associated with improved mobility and reduced fatiguability, with both associations being statistically significant.

Researchers said the findings “demonstrate the efficacy of a behavioral intervention for [people with MS] and obesity.”

CPAP machines reduce fatigue in people with MS and sleep apnea

Use of a continuous positive airway pressure (CPAP) machine can improve fatigue and quality of life over the long term in people with MS and obstructive sleep apnea (OSA). This was the conclusion of researchers who conducted an open-label study that followed 28 people with multiple sclerosis and OSA over an average of 2.7 years.²

All of the study subjects had participated in a prior randomized controlled trial of CPAP treatment and had agreed to continue in a longer-term follow-up study. Sixteen of the 28 people used a CPAP device. The other 12 did not use CPAP or any other treatment for their OSA or for the slowed, shallow breathing associated with their apnea. In evaluations conducted after six months or longer, researchers assessed people in both groups using questionnaires and others instruments that measure fatigue severity, sleep quality, and quality of life.

The people using CPAP machines demonstrated improvement from baseline on the Fatigue Severity Scale, the Pittsburgh Sleep Quality Index, and the Multiple Sclerosis Quality of Life-54 (MSQOL-54). By contrast, the people not using CPAP or any other treatment for their OSA showed no significant improvement in those or other measures.

Using sophisticated analytical models, the researchers found that the differences in outcomes between CPAP users and non-users were particularly significant in terms of fatigue severity, morning fatigue, and the physical aspects of quality of life in people with MS.

As the researchers noted in explaining the rationale for their study, obstructive sleep apnea is fairly common in people with MS. These findings highlight one approach for addressing that health challenge and its contribution to another common aspect of MS – fatigue.

Slight increases in five common conditions may be early indicators for autoimmune disorders

Bladder and urinary tract infections, constipation, depression, and sexual dysfunction may be early signs of multiple sclerosis that are present several years before diagnosis of the neurological disease, according to French researchers.³ The researchers analyzed the electronic health records of more than 110,000 people in France and the United Kingdom. The people studied included 20,174 people with MS and 54,790 without multiple sclerosis.

Additionally, the researchers reviewed the records of 30,477 people with Crohn’s disease and 7,337 with systemic lupus erythematosus, which – like MS – are autoimmune inflammatory conditions. The investigators examined the records of people with MS for reports of 113 different conditions or symptoms in the five years before and the five years after they were diagnosed with multiple sclerosis. They then looked at how often those conditions were reported in people with MS compared to people without multiple sclerosis and to people with Crohn’s disease or lupus.

In the five years prior to their diagnosis of MS, people with multiple sclerosis were:

1.5-times more likely than people without MS to report constipation
1.47-times more likely to report sexual dysfunction
1.38-times more likely to have a urinary tract infection
1.22-times more likely to report or be diagnosed with depression
1.21-times more likely to have cystitis (bladder infection)

Those conditions remained more common in people with MS, compared to the general population, in the five years after they were diagnosed with MS. To complicate matters, however, people with lupus and Crohn’s disease also had increased rates of the five conditions in the years prior to the diagnosis of their autoimmune diseases. As a result, the investigators said, the conditions “lack specificity for MS.”

This study, while valuable, underscores the challenges involved in translating research findings into clinical practice. The conditions identified are all fairly common, and the great majority of people with, for example, constipation or a urinary tract infection, will not later be diagnosed with MS. As a result, a report of one or more of these conditions is not, in itself, reason to initiate an evaluation for MS. At the same time, the study is one of many that are slowly but surely painting a more complete picture of the health changes that precede MS, and as more facts and findings accumulate, clinicians eventually may be able to identify concerning patterns that hopefully will facilitate earlier recognition and treatment of multiple sclerosis.

Disappointing news on Vitamin D and MS prevention

Scientists have long recognized that having a low level of Vitamin D is a risk factor for multiple sclerosis (MS), but little is known about whether taking Vitamin D supplements can help prevent the disease.

To explore that question, researchers recently conducted a trial to see if giving different doses of oral vitamin D3 to people with a clinically isolated syndrome delayed the time to conversion to definite MS. A clinically isolated syndrome, or CIS, is a single episode of central nervous system (CNS) inflammatory demyelinating symptoms that are indicative of MS. Two-thirds or more of people who experience a CIS will go on to clinically definite MS in subsequent months or years.⁴

The study, conducted in Australia and New Zealand, included 199 people with high-risk CIS, meaning that magnetic resonance imaging (MRI) had identified three or more lesions on their brains and/or spinal cords. Study participants were randomly assigned to receive a placebo or 1,000, 5,000, or 10,000 international units (IU) of vitamin D3 daily.

After 48 weeks, 58% of the study participants had converted to MS. In comparing outcomes in people matched by age, sex, baseline symptoms, use of steroids, and other factors, the researchers did not identify significant differences between the people who received placebo and those who received different doses of Vitamin D3.

People taking 1,000 IU/d of the vitamin were somewhat less likely than those on placebo to have converted to MS, while those taking 5,000 IU/d or 10,000 IU/d of Vitamin D3 were somewhat more likely than the placebo group to have converted to MS. Vitamin D3 supplementation was safe and well-tolerated across doses, researchers reported.

“We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high risk clinically isolated syndrome,” the investigators concluded.

Cell therapy for treatment-resistant progressive MS receives FDA Fast Track designation

The FDA this month granted Fast Track designation to a cell therapy being evaluated for the treatment of refractory (treatment-resistant) progressive MS, among other disorders.⁵ The investigational medication, KYV-101, is a chimeric antigen receptor T-cell (CAR-T) therapy being developed by Kyverna Therapeutics, a biopharmaceutical company.

CAR-T therapy is a sophisticated form of immunotherapy being used to treat many cancers and several autoimmune conditions. With these therapies, blood is taken from the patient so that their T cells, which are white blood cells that play a key role in the body’s immune responses, can be isolated. A gene for a receptor – known as a chimeric antigen receptor, or CAR – is added to the T cells to enable them to attach to a specific cell antigen and thus better fight a particular condition. The treated T cells are then reintroduced to the patient through intravenous infusion.

KYV-101 is an autologous (meaning taken from the patient), fully human chimeric CAR-T therapy that targets CD19, a protein expressed on the surface of B cells. Like T cells, B cells are white blood cells that play a role in immune function. They have been implicated in the development of MS.

The FDA Fast Track designation was announced January 19, roughly two weeks after the FDA gave Kyverna Therapeutics clearance to evaluate KYV-101 in a Phase II trial that will enroll people with progressive forms of MS who are not responding satisfactorily to currently available treatments.⁶ Fast Track designation is an FDA program intended to facilitate and expedite the development and review of new drugs to address an unmet medical need in the treatment of a serious or life-threatening condition. Kyverna Therapeutics is also conducting clinical trials of KYV-101 in patients with lupus nephritis and is preparing trials of the cell therapy in systemic sclerosis and myasthenia gravis.

Study finds that internet-delivered therapy reduces depressive symptoms in MS

Participating in internet-based cognitive behavior therapy (CBT) can ease depressive symptoms in people with MS, according to researchers.⁷

CBT is a form of psychological treatment that helps people identify and change faulty or unhelpful ways of thinking and counter-productive behavior. Studies have shown its effectiveness in treating anxiety, depression, marital difficulties, drug and alcohol use problems, and other conditions.

The researchers conducted a Phase III randomized, controlled trial involving 279 people from Germany and the United States who had been diagnosed with MS and who had symptoms of depression. Study participants were randomly assigned in a 1:1:1 ratio to one of three groups.

The first group participated in an internet-delivered CBT (iCBT) program specifically designed for people with MS. The program has 11 modules, which each take 30 to 60 minutes to complete. Rather than talk with a therapist, users answer specific written questions, and the program uses that information to tailor the presentation of content to an individual’s responses. Simulated “discussions” then follow, but with information presented via text rather than through oral conversation. This first cohort of patients was termed the “stand-alone iCBT” group.

The second group also participated in the internet-based CBT program. In addition, however, its members had scheduled email contact with a therapist. This group was termed the “guided iCBT” group. The third cohort of patients received treatment as usual and served as a control group, although its members were offered subsequent access to the iCBT program.

The study’s primary endpoint was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at Week 12 after randomization. People in both the stand-alone iCBT and guided iCBT groups had significantly reduced depressive symptoms compared with the control group at the 12-week mark. Three participants in the control group had clinically relevant worsening of depressive symptoms, as did one in the stand-alone iCBT group. No patients in the guided iCBT group reported such worsening. No occurrences of suicidality were seen during the trial.

Noting that up to 25% of people with MS can experience major depressive disorder in any 12-month period, the study’s authors wrote, “This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers.”

Mapping geographical disparities in access to MS care

Dealing with MS can be difficult no matter where you live, but a recent study shows that obtaining care for the condition can be far more challenging in some parts of the United States than others.⁸

Researchers looked at more than 70,000 US Census Bureau geographic areas, known as census tracts, to see how many were within 60 miles of a neurologist or a multiple sclerosis center. More than 17,800 census tracts, or roughly one-quarter of the total, were not within 60 miles of an MS center. More than 380 were located 60 miles or more from the nearest neurologist.

As might be expected, many of the tracts that were far from a neurologist or MS center were in rural areas. The researchers also found that the census tracts located far from neurologists tended to have higher percentages of Hispanic people, individuals with hearing and vision difficulties, uninsured people, and people with walking difficulties compared to areas with greater access to neurology specialists.

Conversely, tracks with greater access to neurologists and MS centers had relatively higher percentages of people without a vehicle (perhaps indicating that they live in major cities with public transportation systems), people with computers, and people with college degrees. Tracks with greater access to neurologists and MS centers also included a larger African American community (compared to tracks will less access) as well as a larger community of people with limited English language skills.

Efforts to eliminate disparities in MS care rightly have focused on factors such as race/ethnicity and insurance status. This study identifies another disparity that needs to be addressed, one that – quite literally – will require “going the distance” to find solutions.

MS associated with increased risk for thyroid disease

People with MS – and particularly women who have the neurological condition – are at increased risk for thyroid disease relative to the general population. This finding emerged from an analysis of 13 studies that reported data on 13,012 people with MS and another 56,850 people without MS who were included in the studies for comparative purposes.⁹

Researchers evaluating the studies found that people with MS were 1.6-times more likely than the general population to be diagnosed with some type of thyroid disorder, were 1.7-times more likely to be diagnosed with autoimmune thyroid disorder, and were at more than double the risk of others for hypothyroidism – commonly known as underactive thyroid. All of those differences were statistically significant.

Further, the researchers found that the prevalence of thyroid disorders in women with MS was 2.4-times greater than that in men with MS, with that difference also being statistically significant. It should be noted, however, that the American Thyroid Association reports that thyroid disorders are more common in women than in men generally.¹⁰

Thyroid disease may contribute to the severity of two common symptoms of multiple sclerosis – fatigue and heat intolerance. Both are also associated with untreated thyroid disorders. For that reason and others, it is important for people with MS to work with their primary care providers and other clinicians to identify and manage any thyroid problems.

Study characterizes safety and efficacy of Kesimpta^® over the long term

Kesimpta^® (ofatumumab) is a disease-modifying therapy (DMT) approved by the United States Food and Drug Administration (FDA) in August 2020 for the treatment of relapsing forms of MS. The medication, which is given by subcutaneous injection, secured FDA approval on the basis of the Phase III ASCLEPIOS I and ASCLEPIOS II clinical trials. Those trials collected data on people treated with Kesimpta or a comparator DMT, Aubagio^® (teriflunomide), for up to 2.5 years. Recently, researchers added to the evidence based on the efficacy and safety of Kesimpta by publishing results from the ALITHIOS trial, an open-label study conducted to provide longer-term data on the DMT.¹¹

In examining the efficacy of Kesimpta, investigators assessed data on 1,367 patients. Of those, 690 received Kesimpta in one of the initial Phase III studies and then continued the medication in the open-label study. The other 677 study subjects had received Aubagio in a Phase III trial and then switched to Kesimpta in the open-label study.

Among study participants who received Kesimpta in both the Phase III and open-label studies, the annual relapse rate (ARR) was 0.11 during the Phase III study and 0.05 in the extension study, with data extending out to four years. An ARR of 0.05 translates into having one relapse every 20 years. By comparison, people who received Aubagio in the Phase III trial and then switched to Kesimpta had an ARR of 0.23 in the Phase III study and an ARR of 0.06 in the open-label study – a 71% reduction in relapse rate following their initiation of Kesimpta.

The researchers also assessed the safety of Kesimpta in 1,969 patients who had received at least one dose of the medication in any one or more of five trials of the DMT. No new safety signals emerged from their analysis, and researchers said that their findings were consistent with the results of earlier studies. Eighty-six percent of patients receiving Kesimpta reported at least one adverse event, with 12.3% of those events being considered serious and 6.5% leading to discontinuation of the medication. The most commonly reported adverse events were infections (most often upper and lower respiratory infections, urinary tract infections, skin infections, and herpes reactivation), which were reported by 58.4% of study participants.

Looking at their findings as a whole, the researchers concluded, “Ofatumumab has a favorable longer-term benefit-risk profile.”

How MS disease course differs by timing of onset

Compared to people diagnosed with MS at younger ages, people diagnosed at age 50 years or older are more likely to be male, to have primary-progressive MS, to have gait-related initial symptoms, and to have a greater level of disability at diagnosis.¹²

Researchers reported those findings after analyzing UK MS Register data on more than 17,000 people with MS. Slightly more than 9% (n=1,608) were diagnosed at or after age 50, and so were considered to have late-onset multiple sclerosis (LOMS). Just over 15,500 of the people studied were diagnosed between ages 18 and 49, and so were termed as having adult-onset multiple sclerosis (AOMS).

Focusing on study subjects with relapsing-remitting MS, the investigators found that use of disease-modifying therapies (DMTs) was comparable between the two groups, with 44.7% of people in the LOMS group and 44.3% in the AOMS group taking those medications during the study. However, there was a considerable disparity in the proportions of people taking high-efficacy or moderate-efficacy DMTS, which were used by only 17.0% of people with late-onset MS versus 24.6% of those with AOMS. That difference was statistically significant.

The lower use of high- and moderate-efficacy DMTs in people with late-onset MS is noteworthy given the finding that those people tend to have a greater degree of disability at time of diagnosis.

Commenting on the results of their database analysis and of a smaller, autopsy-based study that characterized differences in the brain pathology that marks LOMS and AOMS, the researchers wrote, “The more progressive nature of older-onset MS is associated with significant neurodegeneration, but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people.” By expanding clinicians’ understanding of how MS presents and progresses in different groups of people, research such as this paves the way for greater individualization of care and helps identify opportunities to enhance that care.

Does breastfeeding reduce the risk of developing MS?

Being breastfed for four months or longer may reduce subsequent risk for developing multiple sclerosis in males who have close relatives with MS.¹³ In this study, a reduction in risk was not observed in breastfed females who have close relatives with MS, however, as the investigators note, further studies are warranted. Researchers reached these conclusions after conducting a case-control study that drew on data from a Serbian MS registry as well as information from a control group of people who do not have MS. The study involved 393 people.

One-third, or 131 of those individuals, were classified as having familial multiple sclerosis (fMS), meaning that in addition to having MS themselves, they had at least one relative with MS. Another one-third of people were characterized as having sporadic multiple sclerosis (sMS), meaning that while they had MS, they did not have any relatives who had been diagnosed with the disease. The remaining one-third of people were spouses of the study subjects with MS. They did not have multiple sclerosis and served as a control group for comparative purposes.

Study investigators used a questionnaire to gather information on breastfeeding in infancy and other aspects of the study subjects’ health and lives. They then employed multinomial regression analysis – a sophisticated statistical technique – to identify the relative risk for MS associated with various personal characteristics. They also examined their data by factors such as sex.

Following those analyses, the researchers found that exclusive breastfeeding (meaning not using formula to supplement the nutrition provided by breastfeeding) for four months or longer provided protection against MS in males who had relatives with multiple sclerosis. Researchers did not find that breastfeeding had a protective effect in people with sporadic MS.

Those results, while intriguing, warrant some caveats and commentary. First, while the study was not small, it was not large, either, and because it drew on data for people from a single country, its findings may not be generalizable to a larger population. Second, familial MS represents a minority of cases of the disease, and the finding that any protective effect is limited to males with a close family member with MS – and does not include females – reduces by one-half the proportion of people who might benefit from exclusive breastfeeding. Nonetheless, the study opens a vista into a new area of inquiry as investigators continue to identify factors that increase or reduce risk for MS.

References

1. Bruce JM, Cozart JS, Shook RP. Modifying diet and exercise in multiple sclerosis (MoDEMS): a randomized controlled trial for behavioral weight loss in adults with multiple sclerosis and obesity. Mult Scler. 2023 Dec;29(14):1860-1871.

2. Mazerolle M, Kimoff RJ, Khadadah S, et al. Long-term effects of continuous positive airway pressure treatment of obstructive sleep apnea-hypopnea syndrome in multiple sclerosis patients. Mult Scler Relat Disord. 2023 Nov 20:81:105144. doi: 10.1016/j.msard.2023.105144. Online ahead of print.

3. Guinebretiere O, Nedelec T, Gantzer L, et al. Association between disease and symptoms diagnosed in primary care and subsequent specific risk of multiple sclerosis. Neurology. 2023;101(24):e2497-e2508.

4. Butzkueven H, Ponsonby A-L, Stein MS, et al. Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome. Brain. December 2023. Accepted manuscript provided online ahead of publication. https://doi.org/10.1093/brain/awad409.

5. Kyverna Therapeutics. Kyverna Therapeutics granted FDA Fast Track Designation for KYV-101 in the treatment of patients with refractory progressive multiple sclerosis
Emeryville, CA. Jan. 19, 2024. Available at https://kyvernatx.com/press-releases/kyverna-therapeutics-granted-fda-fast-track-designation-for-kyv-101-in-the-treatment-of-patients-with-refractory-progressive-multiple-sclerosis/. Accessed January 20, 2024.

6. Kyverna Therapeutics. Kyverna’s KYV-01 receives U.S. FDA clearance for treatment of patients with refractory progressive multiple sclerosis in the KYSA-7 Phase 2 trial. Emeryville, CA. Jan. 3, 2024. Available at https://kyvernatx.com/press-releases/kyvernas-kyv-101-receives-u-s-fda-clearance-for-treatment-of-patients-with-refractory-progressive-multiple-sclerosis-in-the-kysa-7-phase-2-trial/. Accessed January 20, 2024.

7. Gold SM, Friede T, Meyer B, et al. Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled phase 3 trial. Lancet Digit Health. 2023 Oct;5(10):e668-e678. doi: 10.1016/S2589-7500(23)00109-7.

8. McGinley MP, Harvey T, Lopez R, et al. Geographic disparities in access to neurologists and multiple sclerosis care in the United States. Neurology. 2024;102(2): https://doi.org/10.1212/WNL.0000000000207916.

9. Gautam S, Bhattarai A, Shah S, et al. The association of multiple sclerosis with thyroid disease: a meta-analysis. Mult Scler Relat Disord. 2023 Dec:80:105103. doi: 10.1016/j.msard.2023.105103.

10. American Thyroid Association. General Information/Press Room. Available at https://www.thyroid.org/media-main/press-room/. Accessed January 21, 2024.

11. Hauser SL, Zielman R, Gupta AD, et al. Efficacy and safety of four-year ofatumumab treatment in relapsing multiple sclerosis: The ALITHIOIS open-label extension. Mult Scler. 2023 Oct;29(11-12):1452-1464.

12. Knowles S, Middleton R, Cooze B, et al. Comparing the pathology, clinical, and demographic characteristics of younger and older-onset multiple sclerosis. Ann Neurol. 2023 Dec 7. doi: 10.1002/ana.26843. Online ahead of print.

13. Jovanovic A, Pekmezovic T, Mesaros S, et al. Exclusive breastfeeding may be a protective factor in individuals with familial multiple sclerosis. A population registry-based case-control study. Mult Scler Relat Disord. 2023 Dec 19:82:105392. doi:10.1016/j.msard.2023.105392.

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

for the Treatment of Relapsing Forms of MS