MS relapse

Editor’s note: “Need to Know” is a series inspired by common forum questions and comments from readers. Have a comment or question about MS? Visit our forum. This week’s question is inspired by the forum topic “Tremors Caused by MS” from April 30, 2018. What’s shaking? If you…

Tecfidera (dimethyl fumarate) is more efficient at preventing relapses, and has a lower discontinuation rate than Aubagio (teriflunomide), according to a Danish study. The study “Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study” was published in the journal Neurology. Aubagio (marketed by Sanofi Genzyme) and Tecfidera…

An application has been submitted to approve ozanimod as an oral treatment for adults with relapsing forms of multiple sclerosis in the U.S., according to its developer, Celgene. “New oral treatment options with differentiated profiles like ozanimod are needed to help address an unmet need for people with relapsing forms of MS,” Jay Backstrom, MD, Celgene’s chief medical officer, said in a press release. Celgene's New Drug Application has been submitted to the U.S. Food and Drug Administration. Earlier this month, the company submitted a marketing authorization application to the European Medicines Agency covering the treatment of adults with relapsing-remitting MS. “With concurrent applications in the U.S. and EU, we look forward to advancing this promising medicine through the regulatory review process to provide a new option for the treatment of (relapsing MS) in 2020,” Backstrom said. Ozanimod is designed to cause the retention of immune cells in lymphoid tissues, thereby blocking their migration to the central nervous system — brain and spinal cord — and preventing damage to nerve fibers and their protective layer, called myelin. The investigational therapy selectively binds to S1P receptor subtypes S1P1 and S1P5. The NDA application is based on positive findings from two multicenter, double-blind, Phase 3 trials called SUNBEAM and RADIANCE part B. Both studies demonstrated that ozanimod reduced the number of relapses and brain lesions. In the SUNBEAM Phase 3 trial, 1,346 participants with relapsing MS were randomized to one daily dose of 0.92 or 0.46 mg of ozanimod — equivalent to 1 mg and 0.5 mg of the therapy’s HCI formulation — or Avonex (interferon beta-1a, marketed by Biogen) for at least 12 months. Results showed that treatment with ozanimod led to fewer relapses and brain lesions, as well as clinically meaningful improvements in processing speed compared with Avonex. In the Phase 2/3 RADIANCE trial, patients were divided in two parts: in part A, participants received either one daily dose of ozanimod (0.5 mg or 1.0 mg) or a placebo for 24 weeks; in part B, a 96-week open-label extension study completed by 223 patients, those initially on placebo switched to ozanimod. As in the SUNBEAM trial, results of part A of the RADIANCE trial revealed a reduction in the number of brain lesions from weeks 12 to 24, as well as less frequent relapses compared with a placebo. Treatment with ozanimod was safe and well-tolerated. Findings of part B of the study included an increased percentage of patients free of T1 lesions on MRI (magnetic resonance imaging) scans — which refer to areas of active inflammation and disease activity — after two years of treatment, from 58.5–69.0% of patients in part A to 86.5–94.6% of patients in part B. T2 lesions, a measure of the total amount of MRI lesions — both old and new — and relapse rate remained low in patients maintained on ozanimod (more significantly with the higher dose of 1.0 mg), and dropped in those who switched from a placebo. The scientists also analyzed ozanimod’s benefits using data from the SUNBEAM and RADIANCE part B trials, which covered 2,659 patients treated over one to two years. Compared with Avonex, ozanimod reduced the annualized relapse rates — the number of relapses per year — by 42% in the higher dose group and 26% in the lower dose group. Treatment with ozanimod also lessened the relapse rate requiring steroid treatment or hospitalization by 43% (in the 1 mg dose group) and 26% (in the 0.5 mg dose group) compared with Avonex treatment. In addition to MS, ozanimod is also being developed for patients with ulcerative colitis and Crohn's disease, two inflammatory bowel diseases.

Non-contrast MRI Effective in Monitoring Progression of MS, Study Shows There’s been increased interest in the risks versus the benefits of using gadolinium to make lesions more visible on an MRI. The U.S. Food and Drug Administration issued an advisory last year raising the level of…

Treatment with ublituximab continues to be safe and well-tolerated by patients with relapsing forms of multiple sclerosis, according to an extension study of a Phase 2 trial. According to a press release, Edward Fox, MD, PhD, from Central Texas Neurology Consultants, will give the presentation on May 7 at poster session P3: MS Clinical Trials and Therapeutic Research. Ublituximab is an investigational monoclonal antibody being developed by TG Therapeutics to target the immune B-cell marker protein CD20. This leads to the depletion of B-cells from the blood and central nervous system — B-cells are activated during MS relapses. According to the company, ublituximab may be superior to current anti-CD20 treatments in MS, enabling both lower doses and shorter infusion times. Final results of the main TG-Therapeutics-sponsored Phase 2 trial were recently presented at the 4th Annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum, held in Dallas, Texas. Data showed that 93% of the 48 patients enrolled (mean age 40 years) were relapse-free after a 48-week treatment with ublituximab. The annualized relapse rate — the number of relapses per year — was 0.07. In addition, median B-cell depletion was more than 99% throughout 48 weeks. Moreover, 87% of participants showed no evidence of clinical disease. Magnetic resonance imaging showed a complete elimination of T1 lesions at 24 and 48 weeks 24 in all 46 patients analyzed. Mean T2 lesion volume decreased by 10.6% at 48 weeks, compared with the beginning of the study. T1 lesions refer to areas of active inflammation and disease activity, while T2 lesions are a measure of the total amount of lesions, both old and new. Ublituximab was found to be well-tolerated, and did not induce an severe treatment-related adverse events. The most frequent adverse events were infusion-related reactions. No patient had to discontinue treatment due to an ublituximab-related side effect. At the upcoming AAN meeting, Fox will present data on both this Phase 2 trial and its open-label extension, in which 37 patients from the primary study continued receiving one-hour infusions of 450 mg of ublituximab every 24 weeks for an additional 96 weeks. Safety was monitored throughout the study, and disability assessments using the Expanded Disability Status Scale were conducted every 48 weeks. As of October 2018, nearly 30% of participants had completed 48 weeks of treatment in the extension study. Results showed that ublituximab continues to be well-tolerated, with no discontinuations due to adverse events. “The Phase 2 OLE supports that one-hour infusions of [ublituximab] continue to be safe and well tolerated,” the researchers wrote. Of note, five of the eight study authors are affiliated with TG Therapeutics. The team expects additional patient follow-up data from the study to be available by the time of the AAN presentation. According to the scientists, the results support the ongoing Phase 3 ULTIMATE program, which includes the ULTIMATE 1 and ULTIMATE 2 trials. These studies are comparing the efficacy and safety of 450 mg of ublituximab with Aubagio over 96 weeks of treatment in relapsing MS patients. Both trials are led by Lawrence Steinman, MD, at Stanford University. TG Therapeutics expects to have results from these trials as early as mid-2020.

Women with multiple sclerosis (MS) do not experience more relapses right after giving birth, as previously believed, according to a preliminary study. The study also revealed that mothers with MS who breastfeed their babies have a lower relapse risk compared with those who do not breastfeed. The data, “…

Treating multiple sclerosis with Tecfidera induces specific genetic alterations that may reduce the levels of immune T-cells targeting the central nervous system, researchers report. Environmental stimuli may induce epigenetic changes in cells — meaning not alterations in the genes themselves, but changes in gene expression (the process by which information in a gene is synthesized to create a working product, like a protein). Epigenetic changes may induce MS development, as these alterations can cause T-cells to attack the central nervous system. One type of epigenetic change is DNA demethylation, the removal of methyl chemical groups, in which molecules involved in metabolism (such as fumarate) interact with enzymes known as DNA demethylases. This process in key for T-cell activation, function and memory, suggesting that it could be an immunomodulatory target. Fumaric acid esters were shown to be effective in MS clinical trials, leading to the approval of Tecfidera (by Biogen) for people with relapsing-remitting forms of the disease. However, their complete mechanism of action remains unclear. Aiming to address this gap, scientists at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York and the Icahn School of Medicine at Mount Sinai, recruited 98 MS patients, either previously untreated (47 people, mean age of 38.4), treated with Tecfidera (35 people, mean age of 42.3), or treated with glatiramer acetate (16 patients, mean age of 43.4) — marketed as Copaxone by Teva Pharmaceuticals, with generic forms by Sandoz (as Glatopa) and by Mylan. All patients had stable disease for at least three months, but disease duration was shortest in untreated patients — 40.4 months vs. 130 months in those given Tecfidera, and 100 months in patients using glatiramer acetate. Blood samples were collected from each participant to assess epigenetic changes in T-cells expressing the cell surface marker CD4. MS patients typically have an activated form of these cells in their blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord. Results revealed that, compared to the other two groups, treatment with Tecfidera was associated with a lower percentage of T-cells containing the CD3, CD4, and CD8 markers, as well as lower levels of subsets of T-cells expressing the CCR4 and CCR6 receptors, which are critical to T-cell migration to the gut, brain, and skin. Treatment with glatiramer acetate resulted in significantly milder alterations in T-cell percentages compared to no treatment. Researchers then found that FAEs induce excessive methylation — the addition of methyl groups — in T-cells containing CD4, compared to glatiramer acetate. Specifically, this overmethylation was observed in a micro-RNA — tiny RNA molecules than control gene expression — known as miR-21, key for the differentiation of a subset of T-cells called T helper-17 (Th17) cells and for CCR6 expression in MS mouse models. These Th17 cells are critical in tissue inflammation and destruction, and have been implicated in MS. The epigenetic effects of FAEs were subsequently validated by comparing pre- to post-treatment with Tecfidera in seven patients. In turn, in vitro (lab dish) experiments showed that FAEs act specifically on the activation of naïve T-cells — those able to respond to new pathogens to the immune system — containing the CD4 or the CD8 markers. Of note, patients with MS have shown increased miR-21 levels, particularly during acute relapses. As such, the team hypothesized that its hypermethylation by FAEs could contribute to remission and the prevention of relapses in this patient population. These results "suggest that the metabolic-epigenetic interplay in T-cells could be harnessed for therapeutic purposes," the researchers wrote, and that the immunomodulatory effect of FAEs in MS is due at least in part to the epigenetic regulation of T-cells. The researchers believe that their findings have a broader implication, beyond MS. "Our findings about therapeutically active metabolites have implications for the treatment of not only multiple sclerosis but also other autoimmune diseases, such as psoriasis and inflammatory bowel disease, which involve the same type of T-cells," Achilles Ntranos, the study’s lead author, said in a press release. "Understanding the epigenetic effect of metabolites on the immune system will help us develop several novel strategies for the treatment of autoimmune diseases, which could help patients and physicians achieve better clinical outcomes," Ntranos added. Patrizia Casaccia, the study’s senior author, concluded: "It may one day be possible to target and suppress production of the specific brain-homing T-cells that play a role in the development of MS."

Full results of a Phase 2 clinical trial testing TG Therapeutics’ lead candidate ublituximab (TG-1101) for relapsing multiple sclerosis (MS) showed that treatment for 48 weeks resulted in a marked reduction of brain and spinal cord lesions, an almost complete depletion of relapse-associated immune B-cells, and significantly halted disability…

Evobrutinib, Merck KGaA’s oral candidate for relapsing multiple sclerosis (MS), is safe and can significantly reduce active brain lesions over 24 weeks of treatment, results of ongoing Phase 2 study show. Xavier Montalban, PhD, MD, with Vall d’Hebron University Hospital in Barcelona, presented the results in the talk “Primary…

The U.S. Food and Drug Administration (FDA) has agreed to review Alkermes’ request to approve diroximel fumarate (BIIB098) as a treatment for relapsing forms of multiple sclerosis (MS), the company announced. A final decision by the FDA is expected in the fourth quarter of 2019. If approved, diroximel…

Stable patients with multiple sclerosis (MS) who transition from Tysabri (natalizumab) treatment to Aubagio (teriflunomide) have a lower relapse risk, a new study shows. The study, “Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy,”…

Relapses can be sneaky. They can scythe you down. I’ve been dealing with multiple sclerosis (MS) since 2006 and I only consciously remember two relapses. The first relapse was two years after I had been diagnosed with sclerosis. There was the possible hope from my first neurologist that nothing…

Multiple sclerosis patients who began treatment with Gilenya and stayed with it continuously showed a more than 50 percent reduction in annual relapse rates, a real-world study following these people for up to three years found. Gilenya, marketed by Novartis, is an oral disease-modifying treatment for relapsing-remitting multiple sclerosis , approved in 2010. It acts by binding and modulating receptors — called sphingosine-1-phosphate receptor — on lymphocytes (adaptive immune cells). By binding to these receptors, Gilenya prevents lymphocytes from leaving the lymph nodes and reaching the brain and spinal cord, and so lower lymphocyte-induced inflammation and damage. Although several clinical trials have reported reduced annualized relapse rates (ARRs) upon treatment with Gilenya, few long-term real-life studies have examined the relapse rate reductions over a long term. A team, led by Novartis researchers and a scientist at Central Texas Neurology Consultants, collected MS patient data from the MarketScan database, a U.S. claims database including medical and pharmacy claims (bills submitted to health insurance providers), between 2009 and 2016. Among 9,312 MS patients in the database with at least one filled Gilenya prescription, 1,599 adults (mean age, 46) met the study's inclusion criteria, including having at least one inpatient or two outpatient claims, and a total of four years of continuous health plan enrollment. Among these 1,599 patients, all used Gilenya for one year (cohort 1), 1,158 (72.4%) took Gilenya continuously up to the start of year two (cohort 2), and 937 (58.6%) used the therapy up to the start of year three (cohort 3). Baseline analysis — measures taken at the study's start — showed that the most common MS-linked symptoms were disorders of the optic nerve and visual pathways (reported in 22-24%), followed by fatigue/malaise (20-21%). Hypertension (20-21%) and depression (15-16%) were the most common physical and mental comorbidities, respectively. The mean annualized relapse rates (AARs) at baseline in these three groups of patients — cohorts 1 to 3 — ranged between 0.48 and 0.51. A consistent reduction in ARRs was seen in all three groups: cohort 1 had a 0.25 ARR at the close of the first year, for a 51% reduction from the baseline rate; cohort 2 a 0.22 ARR at the start of year two, for a  54% lowering in relapse rates from baseline; and cohort 3 had 0.23 ARR at the third year, amounting to a 53% reduction. As expected, when researchers calculated ARRs among patients with continuous Gilenya use over these three years, they found a greater reduction in annual relapse rates. Mean ARRs in continuous-use patients were 0.19 (a 61% reduction) during the first year, 0.18 (a 62% reduction) during the second year, and 0.18 (a 61% reduction) at the start of the third year. “This retrospective claims database study found that patients with MS who received fingolimod [Gilenya] therapy experienced a durable and sustained reduction in relapse rates over a 3-year period,” the researchers wrote, with findings representing “a durable reduction in relapse rates by [more than] 50%.” Reasons that some patients discontinued treatment were not a focus of this study, they added.

Treatment with Ocrevus (ocrelizumab) has superior or comparable effectiveness and a similar safety profile to other available disease-modifying treatments (DMTs) for treating relapsing multiple sclerosis (MS), according to a new review study. The research, “Systematic review and network meta-analysis comparing ocrelizumab with other treatments for…

My readers have recently brought something to my attention: They informed me that not all MS exacerbations (flare-ups, relapses, and attacks) are created equal. I have learned that along with the hardcore types, which usually require steroid treatment, there are also pseudo-exacerbations. I can always trace the causes of…

Relapsing-remitting multiple sclerosis (RRMS) patients on Gilenya (fingolimod) have fewer relapses and stay on treatment longer than those taking Tecfidera (dimethyl fumarate) or Aubagio (teriflunomide), according to a new study. The research, “Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis,” was published…

At the beginning of each year, I reflect on the one that has just passed. In this column, I’m looking back on my multiple sclerosis (MS) columns from 2018, at some of the most popular topics, and how they affect those of us with MS. My column’s year…

Pretreating multiple sclerosis patients with antihistamines more extensively and with hydration can significantly reduce — by 60% — the likelihood of infusion-associated reactions that are the most common side effect of Ocrevus (ocrelizumab) use, a pilot study reported. Data also found that older and male MS patients are less likely to have…

Many years ago a woman I know who has multiple sclerosis (MS) became pregnant. After her child was born her MS became significantly worse. There have been many studies on the impact of pregnancy on someone with MS, with most concluding that the number of MS relapses are…

Multiple sclerosis (MS) patients who have been relapse-free while using an interferon-beta (IFN-β) therapy but switch to another IFN-β are significantly more like to start experiencing flares than patients who remain on their initial interferon treatment, a real-world study reports. Its results support letting patients remain on a current IFN-β medication…

Living in the U.S., where disease-modifying therapies (DMTs) seem to be prescribed as a matter of course to people with multiple sclerosis (MS), I was surprised that it doesn’t seem to be the case across the pond in the U.K. An article just published on the Multiple…

Tysabri (natalizumab) was found to be superior to interferon beta (IFN-β) in a small, 12-month study with relapsing-remitting multiple sclerosis (RRMS) patients, significantly decreasing their disability levels, its researchers report. A vast majority — 90 percent — of Tysabri-treated patients experienced no relapses during the study period,…

A potentially life-threatening case of bleeding in the lungs has been reported and attributed to treatment with Lemtrada (alemtuzumab) by a woman with relapsing-remitting multiple sclerosis. Her medical team found diffuse alveolar hemorrhage in this patient — which resolved in about a week without treatment. The scientists advised that clinicians be alert…

Patients with relapsing-remitting multiple sclerosis (RRMS) on Rebif (interferon beta 1-a), using the RebiSmart autoinjector, have high treatment adherence, despite seasonal weather or temperature fluctuations, as well as fewer relapses over one year, a real-world study reports. The study, “Seasonal adherence to, and effectiveness of,…

I remember the feeling of having a terrible cold or flu before I had multiple sclerosis (MS). The stuffy nose that made breathing nearly impossible. That elusive tickle in the back of my throat combined with a hacking cough. Cold and flu season is a miserable time, and I…

The U.S. Food and Drug Administration (FDA) has issued a safety alert, warning about a rare but life-threatening risk of stroke and artery rupture in patients with relapsing forms of multiple sclerosis (MS) being treated with Lemtrada (alemtuzumab). Since Lemtrada’s approval in 2014 to treat relapsing MS, 13…

So, “it” started on Monday. I have no idea what I’m dealing with. Is it a urinary tract infection, a relapse, a bird, or a plane? The superhero metaphor is warranted because, just like in “Avengers: Infinity War,” there will be no resolution by the end. Hmm, I’ve…

The U.S. Food and Drug Administration (FDA) has issued a safety alert, warning that people with relapsing multiple sclerosis (MS) who stop using Gilenya (fingolimod) may experience disease worsening beyond that when starting the medicine or while taking it. Reported cases of such increases in MS disability upon stopping treatment are…

I’ve never liked carnival rides (except for roller coasters) because they make me dizzy. Walking sideways, feeling nauseous, and turning green is not my idea of a fun time! So, I go out of my way to avoid anything that can make my head spin. Yet, for some reason,…

Relapse rates in women with multiple sclerosis (MS) decline during pregnancy, as does the use of disease-modifying therapies, before both adjust to pre-pregnancy levels again, a large U.S. study based on real-world data shows. The study, “Relapses and disease-modifying drug treatment in pregnancy and live birth…