What’s New in MS Research: Highlights from the 2018 ECTRIMS Annual Meeting

For more than three decades, multiple sclerosis (MS) experts from around the world have gathered in a European city each fall to share the results of their research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). This year’s gathering was held in Berlin, Germany, October 10-12, where the findings were presented from hundreds of studies on topics ranging from the safety and effectiveness of investigational medications to the role of diet in controlling symptoms of MS.

Along with the annual meetings of organizations such as the American Academy of Neurology (AAN), the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), and the Consortium of Multiple Sclerosis Centers (CMSC), the ECTRIMS meeting is an important forum for researchers and clinicians to compare notes, generate hypotheses, make plans for future research, and discuss how best to translate study findings into improved patient care.

This ECTRIMS 2018 research update article highlights more than 30 studies with important implications for people with MS. While these studies represent only a small sampling of the research presented at ECTRIMS, they were selected for their relevance to the current and potential near-term management of MS, and with a view toward addressing a variety of topics. Accordingly, the study findings reported below are organized into eight categories:

FDA-approved medications – oral

FDA-approved medications – injectable

FDA-approved medications – infused

Investigational agents

MSAA’s presentations

Exercise, diet, and lifestyle

Reproductive health in multiple sclerosis

Other research areas

We hope this information will be of interest and value. For additional information about MS, symptoms, and symptom management, as well as MSAA’s programs and services, please visit mymsaa.org or call (800) 532-7667. Questions for MSAA’s Client Services department may be emailed to MSquestions@mymsaa.org. And as always, please note that your healthcare provider remains your best source of information on the medical and overall management of your MS, and should be consulted with any questions you may have or before making any changes to a treatment regimen or other aspects of your approach to living with MS.

For readers who are not familiar with study protocol, to follow is a helpful listing that provides a brief explanation of the different clinical trial phases.

Trial Phases for Investigating Treatments

Phase I

Phase I studies are primarily concerned with assessing the drug’s safety. This initial phase of testing in humans is done in a small number of healthy volunteers, and is designed to determine what happens to the drug in the human body – how it is absorbed, metabolized, and excreted.

Phase II

Once a drug has been shown to be safe, it must be tested for efficacy. This second phase of testing may last from several months to two years, and involve up to several hundred patients. Phase II studies are often “double-blinded,” meaning that the participants, medical staff, and investigators are not told who is receiving the drug and who is receiving the placebo.

Phase III

In a Phase III study, a drug is usually tested in several hundred to several thousand patients, usually in multiple medical facilities around the world. Phase III studies typically last two or more years. Only after a Phase III study is successfully completed can a pharmaceutical company request FDA approval for marketing the drug.

Phase IV

Phase IV clinical trials are conducted after a drug has been approved. Participants are enrolled to further monitor safety and side effects, while evaluating long-term efficacy.

FDA-approved medications – oral

Ongoing decline in relapse rate seen in long-term study of Gilenya®

People with relapsing-remitting MS (RRMS) who took Gilenya® (fingolimod) for five years or more had low rates of disease activity during that period, with gradually decreasing relapse rates, researchers reported. [Kappos P916]

The investigators drew on data from LONGTERMS, an open-label, single-arm, extension study assessing the ongoing safety, tolerability, and efficacy of 0.5 mg of Gilenya in RRMS patients who had participated in earlier clinical trials of the disease-modifying therapy (DMT).

The LONGTERMS study evaluated 754 patients. Sixty-seven percent of study subjects were women, and the mean time since MS diagnosis was 4.8 years. The annualized relapse rate in the population declined from 0.26 at one year to 0.16 at five years and to 0.14 for those patients for whom data were available at the 10-year mark. Of the 697 patients for whom five-year data was available, 78 percent were free from confirmed disability progression in the six months prior to assessment.

The most common adverse events reported were viral upper respiratory tract infections, headache, and hypertension. The most common serious adverse events were
MS relapse, basal cell carcinoma, and pneumonia.

Charting rise in treatment-satisfaction scores with switch to Aubagio®

Patients switching to Aubagio® (teriflunomide) from other disease-modifying therapies (DMTs) showed improvements in treatment satisfaction up to 96 weeks after switching, researchers reported. [Vermersch P885]

Investigators drew on data from the Phase III TENERE study extension and the non-interventional TAURUS-MS I study. Both studies employed the Treatment Satisfaction Questionnaire for Medication (TSQM), which was administered at baseline and every 24 weeks thereafter in the TENERE extension study, and at baseline and at weeks 12, 24, 48, 72, and 96 in TAURUS-MS I.

More than 650 patients from the two studies switched to 14 mg/day of Aubagio after having been on other DMTs. From baseline (initiation of Aubagio) to week 96, Global Satisfaction scores increased for patients from both studies. The average change from baseline was 9.1 in TENERE and 15.3 in TAURUS-MS I, with both changes being statistically significant.

Tecfidera® altered composition of gut microbiome in 12-week study

Tecfidera® (delayed-release dimethyl fumarate) altered the gut microbiome in relapsing-remitting MS (RRMS) patients who took the oral disease-modifying therapy (DMT) over 12 weeks. [Storm Larsen P960]

The gut microbiome – the milieu of bacteria and other microbes found in the gastrointestinal (GI) tract – is a major component of the body’s immune system. Recent research suggests that the composition of the microbiome, as defined by the presence and number of various microbes, may affect the course of MS.

In a study involving 36 patients with RRMS, 17 types of microbes were significantly altered in MS patients compared with 165 healthy controls. In particular, people with MS had lower levels of Faecalibacterium compared to the healthy controls.

Twenty-seven of the study participants received Tecfidera, while nine received an injectable DMT. At two weeks, subjects receiving Tecfidera reported a worsening of GI symptoms compared to baseline, but this impact on symptoms was not seen at 12 weeks. Meanwhile, at 12 weeks, the Tecfidera patients had an increased abundance of Faecalibacterium. Similar alterations were not seen in the participants receiving an injectable DMT.

Researchers continue to investigate not only the role of the gut microbiome in MS, but also the impact that individual microbes may have on disease course. As those investigations continue, this study adds to the understanding of the interplay between MS medications and the composition of the microbiome. As the investigators note, “It could therefore be speculated that direct effects on the gut microbiome are part of the therapeutic actions” of Tecfidera.

FDA-approved medications – injectable

Exploring treatment outcomes in African Americans relative to Caucasian Americans

Do treatment outcomes on disease-modifying therapies (DMTs) differ between African Americans (AA) and Caucasian Americans (CA)? A team of researchers posed that question in the context of the widely held view that African Americans often have a more aggressive form of MS than Caucasian Americans, and therefore may require more efficacious therapies. 
[Ayeni P675]

To find answers, those investigators conducted a retrospective analysis of the CombiRx study, a randomized controlled trial that evaluated combined use of interferon beta-1a and glatiramer acetate in relapsing-remitting MS. The CombiRx study followed patients for three years.

Eighty-eight percent of the study’s 1,008 patients identified as Caucasian Americans, and 7 percent identified as African Americans. At the start of the study, the AA participants had worse disability and a higher total burden of brain/spine lesions than CA participants. Once on treatment, however, there was no difference in outcomes between the two groups.

While that finding is welcome news, the researchers noted that there is a need to study larger numbers of African-American patients to further explore the relative efficacy of DMTs in the AA and CA populations. They added that research into the causes of disparity in disease burden prior to treatment also is warranted.

Support for early initiation of Betaseron® in clinically isolated syndrome

Starting Betaseron® (interferon beta-1b) sooner rather than later in clinically isolated syndrome (CIS) yields benefits up to 15 years after initiation of the disease-modifying therapy (DMT), researchers report. [Kappos P1748]

Investigators in the BENEFIT 15 study monitored long-term outcomes in people who had CIS and at least two lesions on MRI that were suggestive of MS. In an earlier, related study, those individuals were randomly assigned to receive Betaseron (early-treatment group) or placebo. After either two years or conversion to clinically definite MS (CDMS), patients in the placebo group were offered Betaseron (delayed-treatment group).

Of the 468 participants who had been randomized in the initial study, 261 enrolled in a follow-up study 15 years later. One hundred and sixty one were in the early-treatment group and 100 were in the delayed-treatment group. In the delayed-treatment group, Betaseron had been initiated an average 1.5 years after randomization.

The annualized relapse rate in the full analysis set was 0.18 over 15 years. Notably, however, the risk of relapse in the early-treatment group was 19-percent lower than in the delayed-treatment group, and the risk for conversion to clinically definite MS by Year 15 was 31-percent lower.

The researchers concluded that their results “support a sustained benefit of early intervention in reducing the risk of relapse and conversion to CDMS.”

Tracking the efficacy of interferon beta-1a for up to 10 years

With many people with MS now on disease-modifying therapies (DMTs) for several years, there is an increasing focus on the long-term safety and effectiveness of those medications.

Researchers recently evaluated the ongoing efficacy of one of the first DMTs,
subcutaneous interferon beta-1a, in 1,240 individuals receiving care at four MS centers throughout Italy. [Totaro P912] (In the United States, subcutaneous interferon beta-1a is available as Rebif®.) The primary endpoint of their study was the proportion of patients with no evidence of disease activity (NEDA-3) as measured by clinical relapse, confirmed disability progression, and MRI for brain/spine lesions.

Seventy-one percent of the study participants were women, and the participants’ mean age at the start of treatment was 34.6 years. The patients were followed for an average of approximately 7.5 years. Seventy-four percent of patients remained on treatment at two-year follow-up, just under half were still on therapy at the 5-year mark, and 28 percent were on the medication after 10 years of follow-up.

At two years, 44 percent of patients did not have evidence of disease activity, while 25 percent were free of disease activity at five years and 19 percent were at 10 years. The researchers concluded that those percentages constitute “further evidence of sustained interferon beta-1a efficacy in modifying the natural course of MS.”

Plegridy® use in real-world setting consistent with clinical trial findings

A post-approval, real-world analysis of Plegridy® (peginterferon beta-1a) in 963 patients with relapsing-remitting MS yielded safety and efficacy findings consistent with those from the pre-approval clinical trials of the DMT. [Salvetti P1236]

The interim analysis from the Plegridy Observational Program included data on 242 newly diagnosed individuals and 721 people who had been diagnosed one year or longer before study entry. The newly diagnosed (ND) patients generally were younger than their non-newly diagnosed (NND) counterparts (mean age 37.7 years versus 46.0 years) and had less disability, but had experienced more relapses in the prior year.

Treatment discontinuation rates were similar for the two groups (31 percent for ND patients versus 32 percent for NND patients). The most commonly cited reasons for treatment discontinuation in both groups were adverse effects and lack of efficacy. The most frequently reported adverse effects were redness at the injection site and influenza-like illness.

Eighty-two percent of newly diagnosed individuals and 85 percent of those who were non-newly diagnosed were relapse-free up to two years after starting Plegridy. 

Glatiramer acetate slows disability progression for up to 10 years

Glatiramer acetate, which is marketed as Copaxone® and in generic formulations, including Glatopa®, showed enduring benefit over the course of 10 years of therapy, making it a cost-effective option for long-term treatment of relapsing-remitting MS, according to British investigators. [Giovannoni P1275]

The researchers drew on clinical data and cost-effectiveness models to assess the impact of glatiramer acetate (GA) on patient health and health-system economics. The analysis included 752 people treated with GA and another 898 people with MS who were not treated. The investigators found that, relative to no treatment, GA use led to a 17-percent reduction in disability progression as measured by the Expanded Disability Status Scale (EDSS). Further, among people treated with GA, there was only a 1.2-percent difference in Expanded Disability Status Scale (EDSS) scores in six-year and 10-year data.

The study’s authors concluded that the 10-year analysis “continues to support the long-term efficacy of GA in terms of disability, based on EDSS, and utility with no apparent evidence of a waning in treatment effect” making it highly cost-effective based on prevailing prices in the United Kingdom. 

FDA-approved medications – infused

Reductions in relapse rate, MRI disease activity after three-to-five years of Ocrevus®

Two studies of people with relapsing-remitting MS show that use of the disease modifying therapy (DMT) Ocrevus® (ocrelizumab) for three-to-five years is associated with reductions in annualized relapse rate (ARR) and several MRI measures of disease activity, according to researchers. [Hauser P590, Arnold P588]

The studies followed patients who had participated in the Phase III OPERA I and OPERA II trials that led to FDA approval of Ocrevus. In those 96-week studies, patients were randomized to receive either Ocrevus or interferon beta-1a. Upon completion of the Phase III trials, patients were able to enter an open-label extension study in which they would either continue on Ocrevus, if they had been assigned to receive that medication initially, or switch from interferon beta-1a to Ocrevus if they had been in the comparator group.

Among those who received Ocrevus during the initial two-year trial and for three years afterwards in the open-label extension, the annualized relapse rate (ARR) declined from 0.13 in the year before the open-label extension to 0.07 at Year 3 of the extension (or five years, in total, from starting Ocrevus). For individuals who switched from interferon beta-1a to Ocrevus, the ARR decreased from 0.20 in the year before switching to 0.07 at three years post-switch. At five-year follow-up, the proportion of people with clinically defined disability progression was lower in those who had been on Ocrevus for five years than for those who had taken the medication for three years. [Hauser P590]

Meanwhile, in people who switched from interferon beta-1a to Ocrevus, the adjusted number of T1 gadolinium-enhancing lesions on MRI was 0.48 lesions/scan prior to switching medications, and decreased to rates of 0.007, 0.004, and 0.004 after one, two, and three years, respectively, on Ocrevus. Individuals on Ocrevus for the full five-year period maintained low numbers of lesions on MRI. Compared to patients who started Ocrevus after two years on interferon beta-1a, those treated with Ocrevus from the outset had less brain atrophy as measured by whole brain volume, grey matter volume, and white matter volume on MRI. [Arnold P588]

No MRI disease activity in most study subjects after six years on Lemtrada®

Most people with relapsing-remitting MS who began therapy with Lemtrada® (alemtuzumab) after having received subcutaneous interferon beta-1a in a clinical trial were free of MRI indications of disease activity six years after switching medications, researchers reported. [Oreja-Guevara P1239]

The TOPAZ trial followed 143 patients who initially had received subcutaneous interferon beta-1a in the Phase III CARE-MS study. These individuals entered an initial extension study in which they switched to Lemtrada, which was given in doses of 12 mg/day for five days at baseline, and then 12 mg/day for three days 12 months or more later. The participants were then eligible to enter TOPAZ, an additional five-year extension study. In TOPAZ, investigators had the option of giving these patients additional courses of alemtuzumab or another disease-modifying therapy as they thought necessary.

Eighty-two percent of the participating patients completed Year 2 of TOPAZ (Year 6 after starting Lemtrada). Fifty-seven percent did not receive an additional dose of Lemtrada or another DMT during those six years. The annualized relapse rate at Year 6 after Lemtrada initiation was 0.19 percent. Further, 69 percent of patients were free of MRI disease activity, and 89 percent did not have new gadolinium-enhancing lesions. Meanwhile, safety results were consistent with those seen in Lemtrada-treated patients in the initial CARE-2 study and its two-year extension.

Overall, researchers noted, Lemtrada improved clinical and imaging outcomes in patients who switched to the medication after receiving subcutaneous interferon beta-1a, and those improvements were sustained over six years in the absence of further treatment.

Assessing the long-term safety and effectiveness of Tysabri®

An analysis of more than 6,100 people with relapsing-remitting MS who have taken Tysabri® (natalizumab) for several years shows the long-term effectiveness of the medication and indicates that its safety profile remains consistent with ongoing use, researchers reported. [Kappos P908]

Investigators drew on data from the Tysabri Observational Program (TOP) to characterize the Tysabri patient population and assess the medication’s impact on relapses and other measures of MS activity.

At the time of the analysis, the program included 6,149 participants. Their median exposure to Tysabri was 38 doses, and median follow-up time was slightly over five years. Fifty-two percent of patients had discontinued the medication. The patients’ annualized relapse rate declined by 89 percent while on Tysabri, from 1.99 prior to starting the medication to 0.21. The greatest reduction was seen in the approximately 10 percent of patients who had not taken another disease-modifying therapy (DMT), but those who had taken one or two prior DMTs saw ARR reductions of 93 percent and 87 percent, respectively. Fourteen percent of these individuals experienced at least one serious adverse effect, with infections/infestations being the most commonly reported issues.

Investigational agents

Evobrutinib shows favorable impact on lesion count, relapse rates

Evobrutinib, or M2951, is an orally administered compound being investigated as a potential treatment for immune-mediated diseases including MS, rheumatoid arthritis, and systemic lupus erythematosus. Evobrutinib is an inhibitor of Bruton’s Tyrosine Kinase (BTK), an enzyme that plays an important role in the development and function of immune cells, including B lymphocytes and macrophages.

At the ECTRIMS 2018 meeting, researchers announced 24-week results of a double-blind, randomized, 48-week, Phase II study of evobrutinib in patients aged 18 to 65 years with relapsing-remitting multiple sclerosis (RRMS) or secondary-progressive MS (SPMS) with relapses. [Montalban 2018]

In the study, 267 participants were randomized to receive evobrutinib 25 mg daily, 75 mg daily, 75 mg twice daily, placebo, or open-label Tecfidera® (dimethyl fumarate 240 mg twice-daily. (The Tecfidera group served as a reference arm in the study, and no formal comparisons were made between people in that group and those receiving evobrutinib or placebo.)

The study’s primary endpoint was the sum of T1 gadolinium-enhancing lesions at weeks 12, 16, 20, and 24. The annualized relapse rate (ARR) at 24 weeks was a key secondary endpoint, as were safety assessments. The primary analysis comparing the evobrutinib groups to the placebo group was planned to occur when all randomized patients either reached 24 weeks of treatment or had discontinued the study before that point. Ninety-one percent of patients completed 24 weeks of therapy.

The study met its primary endpoint, with patients in the evobrutinib 75-mg once-daily and 75-mg twice-daily groups having significantly fewer gadolinium-enhancing T1 lesions than placebo patients at each time point studied. For weeks 12-24, the mean total of such lesions was 3.85 in the placebo group, 4.06 in the evobrutinib 25 mg once-daily group, 1.69 in the evobrutinib 75 mg once-daily group, and 1.15 in the evobrutinib 75 mg twice-daily group. The evobrutinib 75 mg once-daily and 75 mg twice-daily groups also had greater reductions in the ARR than placebo. [Merck 2018]

No treatment-associated infections or significant reductions in lymphocyte counts were observed in those receiving evobrutinib. The most common treatment-emergent adverse events, occurring in more than 5 percent of patients, included increased liver-enzyme levels in patients receiving 75 mg of evobrutinib twice daily, but these changes were reversible and did not cause symptoms. [Merck 2018]

French study details impact of biotin on disability measure, walking speed

Biotin is a vitamin involved in energy metabolism and fatty acid synthesis, including the activation of an enzyme in myelin synthesis.

In the MS-SPI study, a high-dose, pharmaceutical-grade biotin known as MD1003 reversed MS-related disease disability in 13 percent of patients with progressive multiple sclerosis (PMS).

To assess the efficacy and safety of MD1003 in a real-world setting, as opposed to in a clinical trial such as MS-SPI, researchers monitored outcomes in primary-progressive MS (PPMS) and secondary-progressive MS (SPMS) patients at a clinic in France. [Ciron P1222]

From January 2016 through May 2018, 220 individuals with progressive MS who were receiving care at the clinic in Toulouse, France, received 300 mg/day of the oral medication. At the ECTRIMS 2018 meeting, researchers presented data on the first 91 patients to complete one year of follow-up. Those patients’ mean age at baseline was 59.5 years. Sixty-two percent were females, and 70 percent had SPMS. The mean Expanded Disability Status Scale (EDSS) score at baseline was 5.9, and their mean timed 25-foot walk time was 50.7 seconds.

At the end of one year of treatment with MD1003, 23 percent of the participants had an improvement in their EDSS score and 23 percent had a 20 percent or greater improvement in the time it took them to walk 25 feet. During the one-year period, 11 percent of patients had active disease, such as a clinically defined relapse, a gadolinium-enhancing T1 lesion on MRI, or both.

Researchers said, “This real-world study supports the growing body of evidence that MD1003 is an effective and safe treatment for PMS.”

Gauging the impact of ozanimod on early and advanced relapsing-remitting MS

Ozanimod is a once-daily, oral immunomodulator that targets two cell-surface receptors, sphingosine 1-phosphate receptors 1 and 5, suspected of playing a role in multiple sclerosis.

The agent was evaluated in two Phase III studies, SUNBEAM and RADIANCE. In SUNBEAM, individuals with relapsing-remitting multiple sclerosis (RRMS) received ozanimod on a daily basis (either ozanimod HCl 1 mg or 0.5 mg) or a weekly injection of interferon beta-1a for 12 months or longer. In RADIANCE, the participants were randomized to the same treatments, but for 24 months. More than 2,600 people participated in the trials.

A post hoc analysis presented at the 2018 ECTRIMS meeting examined how outcomes in SUNBEAM and RADIANCE differed between patients with early RRMS and advanced RRMS. The designation of early MS was based on a composite baseline profile that included three years or less from diagnosis, an Expanded Disability Status Scale (EDSS) score ≤3.5, and use of one or no disease-modifying therapies (DMTs). The early MS group consisted of 1,392 patients, while there were 1,267 people in the advanced MS group. Thirteen hundred and ninety-two patients were included in the early MS group. [Comi P1191]

Key differences between the two groups at baseline included median years since diagnosis (0.5 years for the early group and 5.7 for the advanced group), median EDSS (2.0 versus 3.5), mean relapses within the last year (1.4 versus 1.2), and mean count of gadolinium-enhancing lesions (1.77 versus 1.67).

In both the early and advanced RRMS groups, the annualized relapse rate (ARR) was lower in those who received ozanimod than in patients who received interferon. In the early group, the ARR was 0.149 for those on 1 mg of ozanimod HCI, 0.200 for the ozanimod HCI 0.5 mg patients, and 0.285 for the interferon group. The annualized relapse rates in the advanced RRMS group were 0.217 for ozanimod HCI 1 mg, 0.277 for ozanimod HCI 0.5 mg, and 0.363 for interferon.

MRI measures of disease activity also favored ozanimod over interferon. In both the early and advanced RRMS groups, individuals receiving either dose of ozanimod had lower mean numbers of gadolinium-enhancing lesions and new/enlarging T2 lesions at 12 months than patients receiving interferon.

Surveying real-world experience with treating MS with rituximab

Rituximab is a monoclonal antibody approved by the FDA to treat rheumatoid arthritis and several forms of cancer. Because it depletes B cells, which are key components of the immune system, some neurologists prescribe rituximab to treat MS, although it currently does not have FDA approval specifically for use in MS.

Investigators at the University of Colorado’s Rocky Mountain MS Center examined the safety and effectiveness of rituximab in 125 people with MS. [Vollmer P1237] The participants had an average age of 44 years and had an MS disease duration of slightly more than 10 years. Seventy-two percent were female; 62 percent had relapsing-remitting MS.

With an average follow-up of 40.6 months, most individuals had six or seven rituximab infusions. While on rituximab, 16 percent of participants had infections requiring an emergency department visit, and 11 percent had infections necessitating hospitalization. Thirty-seven percent of patients had an infusion reaction on their first infusion that required interrupting the infusion, but that percentage fell to 14 percent on the second infusion. None experienced an infusion reaction that required hospitalization. Two individuals (1.6 percent of the total) were diagnosed with cancer after starting rituximab.

While on rituximab treatment, 5 percent of patients had a clinical relapse, 2 percent had an enhancing lesion on MRI, and – based on detailed analysis – 8 percent of those with available MRI data had a new lesion on T2 imaging.

Those findings prompted the researcher to conclude that rituximab appears to be a safe and effective option for long-term MS treatment.

Two trials to examine the monoclonal antibody ofatumumab in relapsing-remitting MS

Two Phase III trials will assess the safety and efficacy of the human monoclonal antibody ofatumumab relative to Aubagio® (teriflunamide) in people with relapsing-remitting MS. [Kappos P965] Like Ocrevus® (ocrelizumab), ofatumumab targets the CD20 marker on the surface of B cells.

The identically designed ASCLEPIOS I and ASCLEPIOS II trials have enrolled a combined total of 1,884 patients in 37 countries. Study participants will be randomized to receive either 20 mg subcutaneous injections of ofatumumab every four weeks (following an initial regimen of three 20-mg subcutaneous doses per week in the first 14 days) or 14 mg of Aubagio taken orally once daily. Annualized rate of confirmed relapses is the primary endpoint for both trials. Secondary outcomes include confirmed disability worsening and MRI-related measures.

Enrollment for both studies has been completed. Both employ an adaptive design in which study duration is not fixed over a specified period of time but rather is dependent on reaching a pre-specified number of events.

Phase II study to explore impact of opicinumab in targeted population

Early-phase research into investigational agents often identifies patient groups that have a better response to treatment than other patient types. That was the case in the Phase II SYNERGY study of opicinumab.

Opicinumab is a human monoclonal antibody active against LINGO-1, a protein that exercises an effect on the differentiation and regeneration of central nervous system cells. SYNERGY investigated the infused medication’s safety and efficacy as an add-on therapy to disease-modifying therapies (DMTs) in MS. The study found that a patient subpopulation (defined by disease duration and baseline MRI findings) was associated with an enhanced response to treatment.

The Phase II AFFINITY trial is following up on those findings by taking a closer look at the impact of opicinumab in that patient population. At the ECTRIMS 2018 meeting, researchers provided an overview of the AFFINITY study’s design and demographics. [Zhu EP1619]

AFFINITY is a randomized, placebo-controlled trial that will evaluate the efficacy and safety of 750 mg of opicinumab administered intravenously every four weeks compared to placebo as an add-on to DMTs. The trial will last for 72 weeks.

The population being studied encompasses people aged 18-58 years with relapsing-remitting or secondary-progressive MS who have had MS for 20 years or less and who have Expanded Disability Status Scale (EDSS) scores between 2.0 and 6.0. Further, the study’s inclusion criteria specify a clinical relapse in the last four to 24 months or brain MRI evidence of disease activity in the past two years. Because opicinumab is being studied as an add-on therapy, patients must be stable on interferon beta, dimethyl fumarate, or natalizumab for at least six months. Further, the patients must have brain imaging findings indicative of lower myelin content and more preserved tissue integrity in brain T2 lesions.

The study’s main endpoint is Overall Response Score, an integrated assessment of disability improvement and worsening based on the EDSS and other measures. The study began in September 2017, and remains open to enrollment. Study investigators noted that AFFINITY is expected to enroll approximately 240 participants at roughly 150 sites in about 25 countries.

Assessing the safety profile of cladribine

Cladribine is an oral medication approved for use in several countries for the treatment of relapsing-remitting MS (RRMS). It is not approved for that use in the United States. The medication has an unusual dosing pattern in that it is taken for up to 20 days over the course of two years. It also has an unusual mechanism of action: it targets the immune system’s B cells and T cells, leading to a reduction in the total count of those cells followed by a distinct pattern of “reconstitution” as new B cells and T cells are produced.

At the ECTRIMS 2018 meeting, researchers presented an update on the safety profile of Cladribine Tablets in people with RRMS who took the medication as a monotherapy (without use of other MS agents at the same time). [Cook P875] The study assessed data from three clinical trials and a patient registry, and reported information collected through May 2017.

The analysis included data on 923 patients who received cladribine at a dose of 3.5 mg/kg and 641 patients who received placebo. It focused on the incidence of adverse events per 100 patient-years. The cladribine group had an average age of 36.5 years at study enrollment; two-thirds of the cladribine patients were women.

The rate of serious treatment-emergent adverse events per 100 patient years through May 2017 was 3.88 for the cladribine group and 2.24 for the placebo group. Adverse events occurring at a higher rate in the cladribine group than in the placebo group included abnormally low levels of lymphocytes (a white blood cell) and serious infections, including serious herpes zoster.

Study authors concluded that the updated safety profile “was generally consistent with that from two years prior,” adding, “No new major safety findings were identified in the updated dataset, where patients were followed for up to 10 years.”

Elezanumab: Phase I trial supports the need for larger studies

A small, early-stage study of a monoclonal antibody directed at a new target in MS showed the medication to be well-tolerated, but did not demonstrate a clear-cut impact on symptoms, highlighting the need for further testing in a larger population, the study’s authors said. [Cree P899]

Elezanumab is a humanized monoclonal antibody directed against repulsive guidance molecule A (RGMa), which has been shown to inhibit key processes in neurologic regeneration and functional recovery following inflammation or trauma.

A Phase I placebo-controlled, 29-week study randomized 20 people with MS to one of three treatment groups or to a placebo group. Elezanumab was administered intravenously every four weeks for a total of four doses. Patients in the three active treatment groups received an initial “loading” dose followed by maintenance doses of either 150 mg, 600 mg, or 1800 mg of elezanumab.

Twenty-five percent of all participants reported headaches. Most individuals receiving elazanumab did not report a clinically significant improvement in, or worsening of, MS symptoms. However, testing showed that as levels of elezanumab in the cerebrospinal fluid (CSF) increased, levels of free soluble RGMA decreased, while total RGMA (both free and antibody-bound) increased in step with CSF elezanumab exposure. Investigators concluded that, “Additional long-term studies are required to elucidate elezanumab efficacy in a more robust patient population.”

MSAA’s presentations

Survey results reveal people with multiple sclerosis want more information on preventing brain atrophy

Cognitive changes are a common symptom of multiple sclerosis, affecting more than half of those living with the condition. A new survey examines the topic of brain volume loss, known as brain atrophy, in people with multiple sclerosis. The survey, conducted by the Multiple Sclerosis Association of America (MSAA) and sponsored by Celgene, included more than 1,300 people with multiple sclerosis or someone responding on their behalf.

Based on the survey findings that were presented at ECTRIMS 2018, maintaining cognitive function is the second most common concern for respondents. Only the prevention of physical disability progression was reported more often (45 percent).

The survey findings also suggest that there is a high level of interest in better understanding how brain atrophy may impact disease progression. Sixty-three percent of respondents reported that they have not talked to any member of their medical team about brain atrophy, and only 20 percent reported being moderately or very satisfied with the amount of information available on potential ways to prevent brain atrophy. These study results indicate that additional education on the topic of brain atrophy is an area of interest to the MS community.

Global initiative seeks to improve shared decision-making and communication between healthcare professionals, patients, and care partners

Navigating Multiple Sclerosis (MS) is a global initiative that aims to improve outcomes for people with MS through the global adoption of strategies that optimize therapeutic decision-making. This initiative also aims to improve the way that healthcare professionals, patients, and care partners communicate around benefit and risk in the management and treatment of their disease.

In order to better understand the potential barriers to effective communications and shared-decision making, the Navigating MS Steering Committee developed and distributed a survey to MS healthcare professionals and people with MS to identify potential and perceived barriers to successful shared-decision making in MS practice. A total of 73 neurologists, 104 nurses, and 1,184 individuals with MS have responded to the survey.

Differences in the perception of neurologists, nurses, and people with MS regarding the adequacy of resources required for successful shared-decision making was demonstrated in the data received. Four main areas of contention were identified: lack of education, resources, time, and variable involvement of the interdisciplinary (healthcare) team.

Nurse respondents indicated a perceived proficiency with shared-decision making and adequacy of education and training to fulfil this role. However, 73 percent of people with MS who responded indicated a strong preference for engagement with the neurologist in discussing the benefits and risks of treatment options. There was no clear consensus regarding the degree to which decision-making is accurately a collaborative process within the interdisciplinary team.

Half of the nurses stated that the decisions were shared, although people with MS reported a lot of ambiguity and variation in how actively involved they were in the decision-making process. Despite neurologists stating the main barrier to shared-decision making was lack of time, 49 percent of people with MS strongly disagreed that time was a barrier to shared-decision making, with 60 percent of nurses reporting clinic timeframes as adequate.

The disagreement in perceptions among clinicians and people with MS demonstrates an ongoing need to educate both healthcare professionals and patients on best practices in adopting a shared-decision making approach to discussions around treatment decisions. The Navigation MS initiative has received funding from Biogen, Celgene, EMD Serono, Genentech, Novartis, and Sanofi Genzyme.

Exercise, diet, and lifestyle

Taking steps to reduce fatigue – literally

It might seem paradoxical that people who experience fatigue should exert themselves in order to have more energy, but that is exactly what researchers found when conducting a study of 60 individuals with relapsing-remitting multiple sclerosis and fatigue. [Shalaby P951]

The 47 females and 13 males participating in the study had an average age of 30 years and a baseline mean Fatigue Severity Scale (FSS) score of 56.7. They were divided into two groups, balanced by age, gender and FSS score. People in the first group walked on a treadmill three times a week for six weeks, with the pace increasing from easy to brisk during each session and the duration of exercise increasing from 10-15 minutes initially to 25-32 minutes by the end of the study. People in the second group did not exercise but instead received amantadine, a medication used to treat movement disorders.

While the people who did not exercise had no meaningful change in their FSS scores over the 12-week course of the study, those assigned to the exercise group saw their mean FSS score improve to 35.67 (versus 56.7 for all at the start of the study) at six weeks and to further improve to 29.11 at 12 weeks.

The researchers concluded, “A specially designed walking exercise program with gradual increments in time and speed for 12 weeks can improve fatigue in RRMS patients. A long-term follow-up is recommended to verify the maintained effect on such improvement.”

Securing the long-term benefits of activity in MS: “Keep going!”

Is the improvement in quality of life typically seen in exercise and activity programs for people with MS sustained after those programs end? That is the question a team of investigators posed in a study of 56 women with MS. Their answer: Yes, over the short term; and no, over the long term. [Sadhegi P1274]

The women, who had an average age of 34.5 years, were divided into groups, with some assigned to exercise and others to engaging in leisure-time activities such as making crafts. The women completed surveys to measure their sleep quality, fatigue, and depression, if any, at the start of the study and at several points afterward.

Women in both groups showed improvement in sleep, fatigue, and depression at the end of the study and four weeks after its conclusion. By the 20-week mark after the study, however, MS symptoms had begun to increase, leading the researchers to comment that “continuous exercising appears to be of utmost importance for keeping symptoms of depression, fatigue, and sleep disturbances stably low.”

Encouraging news about the role of diet in MS

There is growing evidence that diet plays a role in the MS disease course, but researchers continue to debate how best to study the issue in a scientifically rigorous manner. One practical concern is whether sufficient numbers of people with MS will be able to adhere to restrictive diets long enough for studies to yield valid results.

A six-month pilot study involving 36 women with MS provides encouraging news in this regard. [Katz Sand P643] The study assigned 18 of the women to the intervention group – and to following a restrictive, modified Mediterranean diet for six months. The women in this group participated in training sessions with a nutritionist and attended monthly meetings to assess and encourage their adherence to the diet. The other 18 participants acted as a control group; they participated in educational seminars.

All 18 women in the intervention group completed the study, with a 90.3-percent mean self-reported rate of adhering to the study diet. At the time of the ECTRIMS meeting in early October, 14 of the 18 women in the control group had completed the six-month study, three more were on track to finish in the weeks just ahead, and there was only one anticipated drop out. Sixteen of the 18 women in the intervention group reported that their overall health had benefited from following the study diet, with 14 women reporting benefit in terms of specific MS symptoms. The intervention group subjects also showed greater improvement than the women in the control group on measures of fatigue and MS impact.

The researchers concluded, “It is feasible to enroll MS patients into a rigorous dietary intervention study requiring significant commitment and randomization and reasonable to expect high adherence to this type of dietary program utilizing educational methods to promote adherence.” They added, “Larger-scale clinical trials to assess the role of diet for symptom management and even as a disease modifier in MS are feasible and warranted.”

Exploring the impact of a high-fat, low-carbohydrate diet on MS

The benefits of a ketogenic diet – a high-fat, low-carbohydrate eating plan – have long been promoted by some people with MS and their physicians, while others have said that there has not been adequate research to support the approach. [Brenton P958]

A recent pilot study sought to add to the knowledge base on the subject by assessing how following a ketogenic diet for six months affected 20 people with relapsing-remitting MS. Researchers reported that no subjects experienced worsening diseases – as assessed by clinical symptoms and brain MRI – while on the diet. Further, fatigue and depression scores improved from baseline, and body-mass index and insulin levels declined. While additional data is being collected, those findings prompted the investigators to conclude that ketogenic diets appear to be “safe, feasible, and well-tolerated” in people with relapsing-remitting MS.

Despite the old saying, misery doesn’t actually appear to love company

The more social support a person with MS enjoys, the less pain is likely to interfere with his or her life – even as the intensity of pain increases. [Jensen P374]

That is the bottom-line finding of a study involving 196 people with MS who reported experiencing pain. Study participants had an average age of almost 54 years; 82 percent were women and 18 percent were men. Researchers assessed the participants’ degree of social support, pain intensity, and pain interference at the start of the study and again after an average of roughly 3.5 years.

As would be expected, as the intensity of pain changed, so did the extent to which pain caused interference in a person’s life. However, the study also found that “higher levels of perceived social support [are] associated with subsequent improvements over time in pain interference in individuals with MS and pain, even when controlling for changes in pain intensity.” In simpler language, the more friends, family members, and other meaningful relationships a person has in his or her life, the less he or she will experience interference from pain, even when the pain is intensified. Conversely, the investigators found that “lower levels of social support prospectively predict increases in pain interference.”

Commenting that their findings “are consistent with other research indicating multiple health benefits from the presence of social support,” the study’s authors noted the importance of investigating means to enhance such support for people with MS who are experiencing pain.

Pain and sleep issues are top reasons for cannabis-based product use in people with MS

Roughly one in five people with MS surveyed by researchers at a Canadian hospital reported using cannabis-based products (CBP) on a regular basis, with pain and sleep problems as the most commonly cited reasons for use. [Schabas EP1696]

Investigators at the University of British Columbia MS clinic distributed surveys on CBP use to 600 patients attending the clinic from January to March 2018. Two hundred and fifty-nine participants completed and returned the survey. Seventy-five percent of the respondents were female, and the most common age range of respondents was 45 to 55 years.

Sixty-one percent of respondents reported never using CBP, and another 16 percent said they rarely did so. Of the remainder, 15 percent reported daily use, 4 percent said they used CBP weekly, and 3 percent said they used CBP on a monthly basis. Researchers noted that responder bias might cause overestimation of CBP use.

Seventy-one percent of regular CBP users said they sought relief from pain with a cannabis-based product. Help with sleep also was cited by 71 percent of respondents. Other reported reasons for use included mood (44 percent), spasticity (40 percent), tremor (11 percent), and bladder dysfunction (9 percent).

Ninety-five percent of regular users said they had obtained relief of symptoms from CBP. More than half (52 percent) had discussed their CBP use with a neurologist; 35 percent had not tried other symptomatic medications.

With the increasing liberalization of state laws regarding use of cannabis-based products for both medical and recreational purposes, CBP is likely to be an increasingly accessible option for more and more people with MS.

Reproductive health in multiple sclerosis

Reassurance on use of DMTs in women pursuing pregnancy

“How will this medication affect my ability to conceive, and to deliver a healthy baby?” It’s a question MS clinicians hear frequently when talking with women of child-bearing age about starting a disease-modifying therapy (DMT).

A recent retrospective analysis by Israeli researchers provides reassuring news with regard to this important concern. [Pardo P936] The investigators examined data on 125 women with relapsing-remitting MS who had a total of 219 live births between 2002 and 2017. They divided the women into three groups: those who were not treated with a DMT in the three months prior to becoming pregnant; those who were treated in the three months prior to pregnancy; and those who were treated during pregnancy.

After adjusting for factors including age, disease severity, and known fertility problems, the researchers found that use of DMTs shortly before and during pregnancy did not affect fertility or pregnancy outcomes. They found no significant differences between women in the three groups in terms of the need for fertility treatment and time to pregnancy, pregnancy outcomes, complications during pregnancy, or incidence of relapses during pregnancy or in the first year following delivery.

The investigators concluded, “The decision regarding DMTs treatment in RRMS patients during child-bearing years should not be influenced by the question of pregnancy in the near future.” However, treatment discussions along with pregnancy planning should always be discussed with one’s healthcare team in advance. Additionally, none of the DMTs have been approved by the FDA for use during pregnancy and certain DMTs may present more of a risk than others.

Sexual dysfunction common in women with clinically isolated syndrome

More than one-half of women with clinically isolated syndrome (CIS), a common precursor to MS, experience sexual dysfunction. That is the main finding of a small study in which Egyptian researchers gathered data from August 2011 to June 2017. [Shalaby P374]

Noting that sexual dysfunction has been reported in between 40 percent and 80 percent of women with multiple sclerosis, the investigators sought to determine the frequency of the condition in CIS. They had 43 women with CIS complete the Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSIQ-19), as well as instruments assessing fatigue, cognitive function, anxiety, and depression.

Fifty-six percent of the women reported at least one manifestation of sexual dysfunction. Eight cited a lack of sexual interest or desire, five reported less intense orgasms, and four said they experienced inadequate vaginal lubrication. Beyond those primary aspects of sexual dysfunction, women also reported that symptoms of CIS – such as urinary and bowel problems and difficulty with concentration – interfered with their sexual function. Lack of confidence about sexuality and fear of rejection also was reported to contribute to sexual difficulties.

Fatigue and depression were significant predictors of sexual dysfunction. Further, women who reported sexual dysfunction were older than those who did not report such difficulties (27.5 years versus 23.1 years), but the two groups did not differ in terms of occupation, educational level, or location of brain/spine lesions on MRI. The investigators noted that four patients reported experiencing sexual dysfunction before the emergence of neurological symptoms of MS.

As researchers continue to “fill in the gaps” on the many facets of CIS, this study points to the importance of patients talking frankly with clinicians about the full range of issues they may be experiencing.

Is menopause a turning point for MS disease course?

Relapse rates declined but disability increased in the years following menopause among 148 women with relapsing forms of MS, suggesting that “natural menopause could be a turning point to a less inflammatory, progressive phase of disease,” according to researchers. [Baroncini P369]

Those findings and conclusions are from an observational study conducted at 16 MS centers across Italy. Women were followed for a period of roughly 3.5 years before and after natural menopause, meaning menopause not brought about by surgical removal of the ovaries. Ninety-three percent of the women received disease-modifying therapies (DMTs) during that period. The annualized relapse rate (ARR) for the women declined from 0.22 before menopause to 0.13 following menopause. However, their scores on the Expanded Disability Status Scale (EDSS) increased from a median of 2.0 at menopause to 2.27 two years later and to 2.46 four years after menopause. On the EDSS, an increasing score reflects increased disability. The investigators noted that the findings are in keeping with the results of earlier research they have conducted with a smaller group of women.

The impact of endocrine (or hormonal) factors on MS is a focus of considerable research, and studies such as this one suggest avenues for further investigation, while also helping clinicians and patients better anticipate changes that may await across one’s lifespan.

Other research areas

Promising results for stem cell therapy in “aggressive MS”

Clinicians long have faced a challenge in treating “aggressive MS” – a term used when one’s MS is marked by frequent relapses and rapid progression of disability. An international study presented at the ECTRIMS 2018 meeting offers hope that removing, treating, and re-infusing a patient’s own hematopoietic (blood-tissue forming) stem cells may be a safe and effective first-line therapy for this uncommon but extremely debilitating type of MS. [Das P230]

The study involved 20 patients treated in the United Kingdom, Sweden, Canada, Italy, and the United States. None had received more than three months of standard DMT treatment before undergoing autologous hematopoietic stem cell transplantation, or AHSCT (with autologous signifying that the cells came from the patient, rather than from a donor).

The patients, who ranged in age from 19 to 52 years, had a median EDSS score of 6.5 prior to treatment. They were followed for a median time of 30 months after transplantation. The median improvement in their EDSS score from pre-treatment to last follow-up was 2.5, which was a statistically significant difference. None had a clinical relapse following transplant. Three patients had new lesions on MRI at their first follow-up visit, but no other new or gadolinium-enhancing lesions were seen on later scans. The investigators reported that, “There were routine toxicities, but no treatment-related mortality.”

The researchers added that the study results demonstrate the potential role of AHSCT as a first-line treatment for aggressive MS. Additional studies will continue to provide answers on the potential benefits and risks of this intriguing experimental treatment.

Low immunization rates against respiratory disease in people with MS

Pneumonia and influenza pose serious threats in the setting of MS, but more than 70 percent of people with MS in an Argentine study had not been vaccinated against either illness, researchers reported. [Chiganer P966]

The investigators noted that age, smoking, severe disability, and use of immunosuppressive medications all increase the risk of respiratory infections, adding that people with MS have a risk three-times higher than that of the general population for contracting community-acquired pneumonia.

Against that backdrop, the researchers conducted an online survey of 220 people with MS and 62 healthy controls. The proportion of people not receiving either the pneumococcal pneumonia or influenza vaccine was high in both groups – 71.4 percent of people with MS and 79 percent of the healthy controls. Among the unvaccinated patients with MS, 80 percent were on a DMT medication, 31 percent smoked or had only recently stopped smoking, 22 percent were aged 50 years or older, and 11 percent had severe disability.

The investigators concluded that the low vaccination rates combined with the high prevalence of risk factors among MS patients underscores the need to develop consensus policies on immunization in people who have MS.

Impact of magnetic stimulation on balance in people with MS

Using a coil held over a person’s head to direct magnetic stimulation to the brain improved balance and walking ability in people with relapsing-remitting multiple sclerosis (RRMS) and a related movement disorder, according to a group of Egyptian researchers. [Shehata P1268]

The investigators studied 43 people with RRMS and truncal ataxia, a condition that can diminish balance and the ability to walk. In the first phase of their study, half of the participants received actual magnetic stimulation while the other half received a sham treatment. In the study’s second phase, all subjects received 12 sessions of magnetic stimulation over four weeks every third month, for a total of 48 sessions. Each session lasted several minutes.

The Berg Balance Scale (BBS) and 10-Minute Walk Test (10MWT) were used to measure the impact of treatment, with patients assessed before, during, and at the completion of treatment. The researchers reported that from the pre-treatment baseline to the last session, participants saw a 36-percent improvement in the 10MWT and a 46-percent improvement in BBS score. These individuals also saw improvement on an imaging assessment of white matter in the brain. The investigators said that the adverse effects of treatment were mild and transitory, with two people reporting nausea, two experiencing dizziness, and three having headaches.

Based on these findings, the researchers said that non-invasive, high-frequency repetitive transcranial magnetic stimulation has a long-term beneficial effect on improving balance in people with MS and ataxia.

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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