What’s New in MS Research – March 2019

The opening months of 2019 saw significant research advances on many fronts in multiple sclerosis (MS). A sophisticated analysis of data using healthcare claims found that the number of people in the United States living with MS is more than twice as high as previously estimated. Dietary studies sounded a cautionary note for people with MS drinking soda and many other sweetened beverages, and a hopeful note on the potential for flavonoid-rich cocoa to reduce MS-associated fatigue. A promising stem-cell therapy is moving forward in the clinical-trials process, while the FDA is considering whether to approve a new disease-modifying therapy (DMT). Additionally, genetic analysis, population-based studies, and other investigations are steadily expanding scientists’ understanding of MS risk factors and physiologic processes, laying the groundwork for new treatments and other interventions.

This edition of “What’s New in MS Research” covers all of those developments and more. Beyond perusing the items that follow, please check the Multiple Sclerosis Association of America’s website periodically for updates on other research advances and comprehensive information on all aspects of living with MS.

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Analysis shows the number of people with MS to be much higher than previously estimated

As many as 913,925 people living in the United States had multiple sclerosis (MS) in 2017, according to estimates derived from an extensive analysis of healthcare claims. That number is more than double the previous estimate of 400,000 affected people in the United States. [Wallin 2019]

Researchers arrived at the higher figure by using a sophisticated algorithm (a step-by-step problem-solving process) to analyze the data found in claims from private, public, and military healthcare systems covering more than 125 million people. Drawing on the claims data, the investigators first calculated that 727,344 people in the United States were affected by MS in 2010. They then extrapolated their findings to come up with a low and a high estimate of the number of people living with MS in 2017. Those 2017 estimates ranged from 851,749 people to 913,925 people, or from 337.9 cases per 100,000 population to 362.6 cases per 100,000. The figures represent the MS prevalence, which is the cumulative number of cases diagnosed over several years among people who are still living. [Wallin 2019]

The analysis also confirmed the long-standing finding that MS is more common in women than men. For 2010, investigators found that MS prevalence was 450.1 cases per 100,000 women versus 159.7 cases per 100,000 men, for a female:male ratio of 2.8-1. Further, the 2010 data showed that MS prevalence was highest in people aged 55 to 64 years, and that MS is more common in the north than in the south, differing from a high of 377.4 cases per 100,000 in the northeast to 272.6 cases per 100,000 in the south. [Wallin 2019]

Our findings suggest that there has been a steady rise in the prevalence of MS over the past five decades, the researchers noted. [Wallin 2019] Correcting lower, inaccurate estimates of how many people are affected by MS is critical as the government, payers, and healthcare systems determine how to allocate resources – including research funds and patient-care staff – to address various conditions and diseases.

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Sugary beverages tied to more severe MS symptoms

Drinking roughly two cans per day of non-diet soda or other beverages sweetened with sugar may be tied to more severe multiple sclerosis (MS) symptoms and greater disability relative to not drinking or seldom consuming such beverages. This conclusion is according to a study involving 135 people with MS. [AAN Feb. 26]

The study focused on how participants’ diets compared to the Dietary Approaches to Stop Hypertension (DASH) diet. The DASH diet recommends whole grains, fruits and vegetables, low-fat dairy products, lean meats, poultry and fish, and nuts and legumes. It also limits foods that are high in saturated fat and sugar. [AAN Feb. 26]

Researchers divided the participants into five groups based on those study subject’s self-reported consumption of soda and sugar-sweetened beverages. The people in the top group drank an average of 290 calories of sugar-sweetened beverages – the rough equivalent of two cans of non-diet soda – per day. The lowest group seldom drank sugar-sweetened beverages. The study found that people with MS who drank the largest amounts of sugar-sweetened beverages were five-times more likely to have severe disability than those in the lowest-consumption group. The top group had an average score of 4.1 points on the Expanded Disability Status Scale (EDSS), while the bottom group had an average score of 3.4 points. [AAN Feb. 26]

MS patients often want to know how diet and specific foods can affect the progression of their disease, noted study author Elisa Meier-Gerdingh, MD, of St. Josef Hospital in Bochum, Germany. While we did not find a link with overall diet, interestingly, we did find a link with those who drank sodas, flavored juices and sweetened teas and coffees. Dr. Meier-Gerdingh added that while the results of the research need to be confirmed by larger, longer studies, We do know that sodas have no nutritional value, and people with MS may want to consider reducing or eliminating them from their diet. [AAN Feb. 26]

The researcher also noted that the study assessed participants diets and sugar-sweetened beverages at the same time as disability, precluding investigators from determining whether sugar-sweetened beverages contribute to higher disability or whether more severe disease affects a person’s ability to follow a healthy diet. [AAN Feb. 26] Further information on the study will be presented at the 71st annual meeting of the American Academy of Neurology, which will take place in Philadelphia, Pennsylvania in early May 2019.

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Meanwhile, a sweet remedy for MS-related fatigue shows early promise

A cup of flavonoid-rich cocoa may someday be just what the doctor orders to help with the fatigue frequently experienced by people with relapsing-remitting multiple sclerosis (RRMS). Flavonoids are a group of more than 5,000 plant chemicals found in fruits and vegetables, and are especially abundant in cocoa and dark chocolate. Flavonoids, which are associated with anti-inflammatory properties, have been previously studied in people with chronic fatigue syndrome. [BMJ March 4]

Researchers in the United Kingdom recently assessed the impact of flavonoids on MS-related fatigue in a randomized, double-blind study that involved 30 women and 10 men with RRMS. Those study participants were randomized to drink either high-flavonoid or low-flavonoid cocoa each day for six weeks. [Coe 2019]

At the end of the study period, the people drinking the high-flavonoid cocoa showed a 45% improvement in subjectively assessed fatigue and an 80% improvement in walking speed. Overall, 11 of the 19 people in the high-flavonoid group and eight of the 21 people in the low-flavonoid group reported improvement in their fatigue. [Coe 2019]

The researchers noted that the mental and physical fatigue experienced by people with MS arise from complex causes, likely involving neural, inflammatory, metabolic, and psychological factors. Flavonoids potentially could be used in conjunction with exercise, medication, and physical therapy to provide a comprehensive approach to managing fatigue in MS, they added. The use of dietary approaches to reduce fatigue and associated factors in people with MS may be an easy, safe, and cost-effective way to have an impact on quality of life and independence, allowing people to feel more in control of their condition, the investigators said in calling for more-extensive research into the potential for flavonoids to reduce MS-related fatigue. [BMJ March 4]

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Clinical trial to evaluate stem-cell therapy for progressive MS

A therapy that would use a patient s own stem cells to treat progressive MS is moving toward the clinical trial stage.

In December 2018, the FDA approved an application from BrainStorm Cell Therapeutics to begin a Phase II clinical trial of NurOwn^® mesenchymal stem cell-neurotrophic factors (MSC-NTF) cells. [BrainStorm] The trial is scheduled to get under way early this year, with an estimated primary completion date of February 2020 and full completion date of September 2020. [clinicaltrials.gov NCT03799718]

The Phase II trial will involve 20 people with progressive MS, and will be conducted at multiple locations. [clinicaltrials.gov NCT03799718] Participants mesenchymal stem cells will first be removed from their bone marrow via insertion of a hollow needle. Those cells then will be converted into MSC-NTF cells by growing them under patented conditions that cause the cells to secrete high levels of neurotrophic factors, which are molecules that support the development and differentiation of neurons. [BrainStorm] The MSC-NTF cells will be re-introduced into the patients bodies through three intrathecal cell transplantations over the course of 16 weeks. [clinicaltrials.gov NCT03799718] Autologous (meaning from the patient’s own body) MSC-NTF cells can deliver neurotrophic factors and other immune-modulating molecules directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease, BrainStorm Cell Therapeutics explained in outlining the rationale for the treatment. [BrainStorm]

Participants will be followed for 28 weeks after the start of treatment, with researchers monitoring for adverse events. The study will also measure the change from baseline to 28 weeks post-treatment in the participants 25-foot walking speed. Sixteen weeks after treatment, researchers will analyze the participants cerebrospinal fluid (CSF) to determine how many individuals had changes in neurotrophic factors in their CSF. [clinicaltrials.gov NCT03799718]

In announcing the FDA’s acceptance of its application to conduct a Phase II study, BrainStorm Cell Therapeutics noted, There are currently no FDA-approved autologous cellular therapies addressing MS or other neurological diseases. The company is also conducting a Phase III clinical trial of autologous MSC-NTF cells for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. [BrainStorm]

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Late 2019 target date for FDA action on potential new treatment for relapsing-remitting MS

The Food and Drug Administration (FDA) has set a fourth quarter 2019 target date to act on an application to approve the oral agent diroximel fumarate to treat relapsing-remitting multiple sclerosis (RRMS). [Alkermes Feb. 25]

In late February, the pharmaceutical companies Alkermes plc and Biogen Inc. announced that the FDA had accepted a new drug application (NDA) for diroximel fumarate. [Alkermes Feb. 25] Biogen currently markets the oral disease-modifying therapy (DMT) dimethyl fumarate in the United States as Tecfidera^®. Biogen and Alkermes note that diroximel fumarate may have the potential to offer differentiated GI [gastrointestinal] tolerability due to its chemical structure as compared to dimethyl fumarate. [Alkermes Feb. 25] The prescribing information for Tecfidera notes that in clinical trials of the agent, 18% of patients reported abdominal pain, 14% reported diarrhea, 12% said they experienced nausea, and 9% reported vomiting. [Tecfidera PI]

The application for FDA approval of diroximel fumarate is based on the results of the Phase III, open-label, two-year safety study EVOLVE-MS-1, along with studies comparing the pharmacologic profiles of diroximel fumarate and dimethyl fumarate. Alkermes is also conducting the EVOLVE-MS-2 study in people with RRMS. That five-week study will compare the GI tolerability of diroximel fumarate with that of dimethyl fumarate. [Alkermes Feb. 25]

If the FDA approves diroximel fumarate, Biogen intends to market the oral DMT under the brand name VUMERITY^™, subject to approval by the FDA, which has conditionally accepted the name. [Alkermes Feb. 25]

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Biogen studying an extended dosing interval for Tysabri^®

Can stretching out the time between doses of Tysabri^® (natalizumab) enable people with relapsing-remitting multiple sclerosis (RRMS) to continue to derive health benefits from the disease-modifying therapy (DMT), while reducing the risk for a rare but serious brain infection, progressive multifocal leukoencephalopathy (PML)?

It is a question that MS researchers have been asking since evidence emerged a few years ago that Tysabri was associated with an elevated risk for the viral infection. Since then, individual MS centers and neurologists have adapted extended-dosing intervals and reported their results to Biogen, the company that markets Tysabri. They in turn have used this information to conduct a retrospective analysis of patients receiving extended-interval dosing (EID) vs. those on the FDA-approved standard-interval dose (SID) of 300 mg every four weeks. [Biogen January 3]

Now, however, Biogen will be comparing the safety and efficacy of six-week dosing to that of the standard four-week dose in a prospective, randomized study that will enroll approximately 480 people with RRMS. In early January, the company announced that it had enrolled the first patient in the two-year, Phase IIIB study, known as NOVA. The global study will evaluate people who switch to the six-week EID after one year on the four-week SID regimen to those who remain on SID. The primary endpoint will be the number of new or newly enlarging T2-hyperintense lesions seen on MRI at 48 weeks of treatment. [Biogen January 3]

Biogen initiated the NOVA study after its retrospective analyses showed that EID was associated with a significant reduction in the risk of PML, the company noted. More than 190,000 people worldwide have been treated with Tysabri. [Biogen January 3]

An analysis of pooled data from more than 37,000 patients participating in four large clinical trials found that fewer than 1% overall had developed PML. [Ho] However, among those who had an antibody known as the anti-John Cunningham virus (anti-JCV) antibody, the estimated cumulative probability of having PML over the course of six years of Tysabri treatment was 2.7% in those who had used an immunosuppressant agent before Tysabri and 1.7% in those who had not received an immunosuppressant previously. [Ho]

The NOVA study may generate valuable data that we hope will answer questions for the scientific community about the efficacy of nataliuzumab when its dosing schedule is extended to every six weeks, and in conjunction with prior safety analyses, may inform on the drug’s benefit-risk profile, noted Alfred Sandrock, MD, PhD, Biogen’s executive vice president and chief medical officer. [Biogen January 3]

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News on disease-modifying therapies and pregnancy

Use of a disease-modifying therapy (DMT) early in pregnancy does not appear to be associated with a significant risk of miscarriage, preterm delivery, poor fetal growth, or other adverse pregnancy outcomes. That’s the conclusion of a database analysis that evaluated 984,058 pregnancies occurring between 2011 and 2015, including 1,649 pregnancies to women with MS. Thirty-five percent of the women with MS filled a DMT prescription within 90 days before pregnancy. Researchers concluded, Pregnancies with and without early DMT exposure had similar risks of outcomes to one another and to pregnancies in women without MS. [MacDonald 2019]

Please note that while these findings are encouraging, women who are pregnant or are planning to become pregnant while taking a DMT are advised to consult with their physician.

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Rituxan^® and no evidence of disease activity (NEDA) in pediatric-onset MS

Rituxan^® (rituximab) is a monoclonal antibody approved by the FDA to treat rheumatoid arthritis, forms of lymphoma and leukemia, and other conditions. Although it is not approved for use in multiple sclerosis (MS), some neurologists use it off-label to treat their adult MS patients.

Now, a chart review of pediatric-onset MS (POMS) patients treated with Rituxan at Texas Children’s Hospital suggests that the agent is effective in younger people. The analysis examined data on 17 patients who ranged in age from 13 years to 22 years at the time of the chart review. All had undergone magnetic resonance imaging (MRI) six months or longer after starting Rituxan. Their mean age was 18 years, and their mean disease duration was 41 months (close to three and a half years). Four of the study subjects received Rituxan as their first disease-modifying therapy. Nine switched to Rituxan from another DMT because of disease progression, while another four switched to Rituxan after experiencing side effects on an earlier DMT. [Shukla ACTRIMS 2019]

The review found that 82% (14 of 17) of those young patients had no evidence of disease activity (NEDA) as measured by absence of new T2 or contrast-enhancing lesions on MRI, absence of relapses, and absence of increased post-treatment disability. [Shukla ACTRIMS 2019]

While acknowledging that the retrospective nature of the analysis and the small number of patients involved were study limitations, the authors nonetheless noted that our data supports the use of rituximab in POMS and suggests high rates of NEDA in this population. [Shukla ACTRIMS 2019]

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Can reducing children’s weight reduce their risk for MS later in life?

Clinicians long have noted that many people with multiple sclerosis (MS) were overweight as children, but the complex nature of MS makes establishing a cause-and-effect relationship difficult.

Now, however, a team of Canadian and British researchers has found genetic support for childhood obesity playing a role in the development of MS. Those researchers conducted a genome-wide association study involving 14,802 people with MS and 26,703 controls. They identified 22 genetic variants strongly associated with childhood body mass index (BMI) and examined the effect that each variant had on MS. [Harroud 2019]

One key finding: a one-standard deviation (SD) increase in childhood BMI increased the risk of developing MS by 29%. [Harroud 2019] The researchers noted, These findings suggest that targeting childhood obesity may be an effective strategy to reduce MS incidence. [Harroud 2019]

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Exploring the link between pediatric MS and a family history of autoimmune disorders

Children and adolescents with multiple sclerosis (MS) are more than twice as likely as other young people to have a close relative with an autoimmune disorder. [Greenberg ACTRIMS]

That finding emerged from an ongoing, multi-center study of risk factors for pediatric MS. The study, which began in 2011, compares the medical data, biologic specimens, and family history of children and adolescents with MS with that of their peers unaffected by the condition. After adjusting for variables such as sex, race, age, and ethnicity, the analysis identified family history of autoimmune disease as a factor associated with an increased risk for developing MS before adulthood. [Greenberg ACTRIMS]

The odds of a pediatric MS patient having either a first- or second-degree relative with an autoimmune condition were 2.27 times that of a young person without MS, according to researchers. They noted that the differences between young people with MS and healthy controls were most marked when there was a family history of diabetes, thyroid disorders, or rheumatoid arthritis. Conversely, no difference in risk was observed when a family member had eczema or psoriasis. [Greenberg ACTRIMS]

Researchers also found that the odds of autoimmune disease among family members was significantly higher on the father’s side of a young person’s family compared to the mother’s side. The investigators noted that this increased prevalence of certain autoimmune disorders in close relatives of pediatric MS patients aligns with prior findings among adult populations. [Greenberg ACTRIMS]

As investigators continue to explore how genetics and immunologic function contribute to the development of MS in children and teenagers, this study adds another piece to a complex puzzle.

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The “economic complications” of MS: unemployment and underemployment

Unemployment and underemployment are common among people with multiple sclerosis (MS), with fatigue being a major obstacle to workplace participation and productivity.

That’s one of the early insights from ongoing research being conducted by the North American Registry for Care and Research in Multiple Sclerosis (NARCRMS). [Rammohan ACTRIMS 2019] The Registry collects a wide range of information on people with MS, and uses that information to examine issues such as the economic impact of MS.

An early analysis of data from 212 NARCRMS patients found that 31% either were unemployed or underemployed. Among those who were employed, almost one-third said that MS affected their work, with fatigue being the leading issue cited. The economic impact of identifying an effective treatment for this disabling symptom of MS cannot be overstated, the study’s authors noted. [Rammohan ACTRIMS 2019]

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Assessing the extent and impact of “stem cell tourism”

“Stem cell tourism” is the latest manifestation of a trend as old as the disease itself offering unproven therapies to desperate patients.

The phenomenon is increasingly prevalent in multiple sclerosis (MS) and other neurologic diseases, according to a team of researchers from Ohio State University. Those investigators recently surveyed academic neurologists across America, and found that 65% had at least one patient who had received unproven cellular preparations. [Rai ACTRIMS 2019] It should be noted that patients receiving such preparation without their physician’s knowledge or against their physician’s advice is entirely different from participating in a stem cell clinical trial that has been carefully designed, approved by hospital officials, registered on clinicaltrials.gov, and meets rigorous ethical, safety, and monitoring standards. [Rai ACTRIMS 2019]

The academic neurologists reported that 33% of their patients had received unproven “stem cell therapies” in the United States, 22% had received their treatment abroad, and 37% had received preparations in both the United States and abroad. Overseas destinations included China, Germany, Mexico, the Bahamas, Russia, and Costa Rica. [Rai ACTRIMS 2019]

Three-quarters of the survey respondents said their patients did not report complications from receiving these unproven preparations. However, among the 25% whose patients did report adverse effects, complications included stroke, meningoencephalitis, quadriparesis, sepsis, hepatitis C, seizures, and infections. At least three respondents had patients who died following these procedures. [Rai ACTRIMS 2019]

The authors said that the complications of these unproven approaches and the overall negative impact on people with MS underscore the need for a comprehensive education campaign to prevent the exploitation of individuals with MS.

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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. Jack Burks, MSAA Chief Medical Consultant

Edited by Susan Wells Courtney, MSAA Senior Writer

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References:

Alkermes plc and Biogen Inc. Alkermes and Biogen announce U.S. Food and Drug Administration acceptance of diroximel fumarate New Drug Application for multiple sclerosis. February 25, 2019.
http://investor.alkermes.com/phoenix.zhtml?c=92211&p=irol-newsArticle&ID=2388731. Accessed March 10, 2019.

American Academy of Neurology. Soda, sugar-sweetened beverages linked to more severe symptoms for people with MS. March 5, 2019. www.aan.com/PressRoom/Home/PressRelease/2701. Accessed March 9, 2019.

Biogen Inc. January 3, 2019. First patient enrolled in Biogen’s Phase 3B study to evaluate extended interval dosing (EID) with natalizumab in multiple sclerosis. http://investors.biogen.com/news-releases/news-release-details/first-patient-enrolled-biogens-phase-3b-study-evaluate-extended. Accessed March 10, 2019.

Biogen Inc. Tecfidera^® (dimethyl fumarate) delayed-release capsules, for oral use [prescribing information]. Cambridge, MA: December 2017.

BMJ. Cocoa may help curb fatigue typically associated with multiple sclerosis (MS). March 4, 2019. https://eurekalert.org/pub_releases/2019-03/b-cmh022819.php/. Accessed March 14, 2019.

BrainStorm Cell Therapeutics Inc. Dec. 17, 2018. FDA accepts BrainStorm’s NurOwn^® IND application for progressive multiple sclerosis. http://ir.brainstorm-cell.com/news-releases/news-release-details/fda-accepts-brainstorms-nurownr-ind-application-progressive. Accessed March 9, 2019.

Coe S, Cossington J, Collett J, et al. A randomised double-blind placebo-controlled feasibility trial of flavonoid-rich cocoa for fatigue in people with relapsing and remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019. doi.org/10.1136/jnnp-2018-319496.

Greenberg B, Casper TC, Harris Y, et al. Family history of autoimmune disorders among pediatric multiple sclerosis patients. P147. Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. February 28 – March 2, 2019. Dallas, TX.

Harroud A, Morrisa JA, Forgetta V, et al. Childhood obesity and multiple sclerosis susceptibility: a Mendelian Randomization study. P120. Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. February 28 – March 2, 2019. Dallas, TX.

Ho PR, Koendgen H, Campbell N, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.

McDonald SC, McElrath TF, Hernandez-Diaz S. Use and safety of disease-modifying therapy in pregnant women with multiple sclerosis. Pharmacoepidemiol Drug Saf. 2019. Doi:10.1002/pds.4735

National Library of Medicine. Safety and efficacy of repeated administration of NurOwn (MSC-NTF cells) in participants With progressive MS. ClinicalTrials.gov Identifier: NCT03799718. www.clinicaltrials.gov/ct2/show/NCT03799718. Accessed March 9, 2019.

Rai W, Yuhasz N, Julian K, et al. Complications of stem cell tourism in multiple sclerosis and other neurological diseases: results from first nationwide survey of academic neurologists. P237. Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. February 28 – March 2, 2019. Dallas, TX.

Rammohan KW, Halper J, Murphy SMc, et al. The economic impact of multiple sclerosis: a preliminary look at the North American Registry for Care and Research in Multiple Sclerosis. P296. Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. February 28 – March 2, 2019. Dallas, TX.

Shukla NM, Lotze T. No evidence of disease activity in the majority of pediatric-onset multiple sclerosis patients receiving rituximab. P047. Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2019. February 28 – March 2, 2019. Dallas, TX.
Wallin MT, Culpepper WJ, Campbell JD, et al. The prevalence of MS in the United States. Neurology. 2019;92:e1-e12.doi:10/1212/WNL.0000000000007035.