CIS

The percentage of Taiwanese who develop multiple sclerosis (MS) after an episode of clinically isolated syndrome (CIS) is lower than that reported for other ethnicities, and those who do progress are likely to have a milder disease course, a study found, supporting how factors like geography and genetics…

A woman’s age at her first menstruation, or becoming pregnant and breastfeeding does not substantially influence the long-term risk of multiple sclerosis (MS) or the risk of increased disability, a study of a large number of patients with clinically isolated syndrome…

When the U.S. Food and Drug Administration approved the disease-modifying therapy Mayzent for relapsing types of multiple sclerosis, it specified in its label that the treatment was for people with clinically isolated syndrome, relapsing-remitting MS, and — importantly — secondary progressive MS provided they have "active" disease. The approval is good news, an MS researcher and physician said to Multiple Sclerosis News Today in an interview, but "surprising" in that the FDA's decision was largely based on a trial that didn't involve CIS patients and wasn't focused on responses among particular types of SPMS. “It's the first time that I've seen in the MS field that regulators made an approval designation — active secondary progressive MS — based on an underpowered subgroup analysis,” said Robert Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic. Novartis' medication, as a first oral therapy approved in the U.S. for a form of SPMS, is a big step forward in MS treatment, he said. But details of the FDA's decision caught him off guard. Fox served on the steering committee for the EXPAND Phase 3 clinical trial , on which the FDA decision was largely based. His clinic was also one of the sites treating and evaluating patients in this pivotal study. Results of the EXPAND trial showed that Mayzent could reduce the risk of disability progression at three months (the trial’s primary endpoint, or goal) by 21% in treated SPMS patients, compared to those given a placebo. Among those with active SPMS (meaning with relapses), a 33% reduction was observed. The treatment, an S1P modulator that works in part to keep lymphocytes from entering the brain to trigger inflammation, also decreased the annualized relapse rate by 55% and improved cognitive processing speed in all treated patients.  “What was found, and I think quite clearly found in a large-size study, was that siponimod in patients with secondary progressive MS clearly slowed the progression of clinical disability over the course of the trial,” Fox said. “It's a statistical concept — obviously patients either progress or they don't progress — but on an overall basis there was a 21% slowing in the rate of progression of clinical disability.” The FDA’s decision is particularly important for SPMS patients. While Ocrevus (ocrelizumab) also treats all relapsing MS forms and people with primary progressive disease (PPMS), it's an intravenous therapy given every six months. Mavenclad (cladribine), approved for relapsing patients in the U.S. just days after Mayzent, is another oral and active disease therapy. To Fox, Mayzent seemed to reach beyond only those secondary progressive patients with clinically active disease. “Really, this is the only drug that's been found to be effective in secondary progressive MS," he said. “To that degree, it stands alone.” That's why two points in the FDA's decision surprised him. The first is the label's specific mention of clinically isolated syndrome. CIS is defined as the first clinical presentation of this disease — a neurological episode that lasts at least 24 hours, and is characterized by inflammatory demyelination (the loss of myelin, the protective coat surrounding neurons).   For clinicians like Fox, CIS is a first manifestation of MS — a kind of "mono sclerosis." Since there’s only one documented attack, it can’t yet be considered multiple sclerosis, “as the multiple hasn't happened,” Fox said, but many "in the field consider CIS to be … an early stage of MS." “If the patient has a whole bunch of lesions on their brain [as seen on an MRI scan] and they had a single clinical event, ah, probably, they have MS,” he said. Regulatory bodies like the FDA, however, have historically considered CIS to be its own separate entity. That makes this decision doubly surprising, according to Fox, since the EXPAND trial only enrolled patients with SPMS, not CIS.   “It's the first time I've seen them approve for CIS specifically when there wasn't a trial in CIS,” Fox said. “I agree with it — I don't have a problem with it — it just surprised me that the regulators were so progressive in their appreciation of MS.” The second — and far more unsettling — surprise was the FDA’s decision to only approve Mayzent for “active” SPMS patients, instead of all SPMS patients. This decision didn’t come out of nowhere, he noted, but it remains puzzling in the context of the EXPAND trial.  In compiling trial results, investigators did a subgroup analysis — as they often do, almost as an aside for research reasons — and found more favorable responses to Mayzent treatment in patients with active inflammation before the trial's start, those it determined to be with "active" disease.   “There was a third of patients who had a relapse in the two years prior to enrollment, and those patients actually had a 30% slowing in disability progression, compared to the 21% overall,” Fox said. This certainly does suggest that Mayzent can be more effective in people with active disease — but there's a catch. The trial itself was not designed to make such a distinction. It enrolled SPMS patients regardless of activity, and its priority goal was changes in disease progression across all who were treated with Mayzent or given a placebo.   “What's important is that the trial was powered for the overall outcome. It was not powered for subgroup analysis,” Fox said, considering this a crucial point.  In clinical studies, being “powered” refers to the enrolling of whatever specific number of participants a study needs to ensure its results will reach statistical significance. More people are redundant and, as such, an unnecessary cost; fewer could mean that trial's conclusions cannot be supported by rigorous scientific measures.  In other words, Fox said, the only conclusions that can be drawn from the EXPAND study reliably — with rigor — are based on data drawn from all its SPMS patients, not a subgroup with active disease. This trial “followed over 1,600 patients for the clinical disability. These are purposely powered so that you're not following twice as many people as you need to … you're powered for that primary outcome,” he said. “So, how could they [the FDA] look at a subgroup analysis and make an approval decision based on a subgroup analysis that was underpowered?” The neurologist gave as examples other subgroup differences found in trial analyses that didn't affect regulatory approval — but to his mind, equally could have. One was an analysis finding female SPMS patients responded to the therapy better than males, showing lesser disease progression. "So why didn't they just approve it for the females and not the males?" Fox asked. But, when asked, Fox did not think the label to necessarily be an error. "My point is the absurdity of it," he said. "How could they make the regulatory approval based on a subgroup analysis that wasn't powered for conclusions?" He was also particularly troubled because the FDA “didn't define what ‘active’ means — is it just a relapse, or is it MRI disease activity?"  For many clinicians, “active” SPMS refers to ongoing inflammation that can be observed on MRI (magnetic resonance imaging) scans. In EXPAND, however, the active subgroup was defined as patients with clinical relapses within two years of being enrolled in the trial. Fox worries about this apparent lack of a regulatory definition of "active" SPMS, since “obviously, the insurance companies are going to seize upon that, and they're going to look for every way they can to avoid covering it for patients.” Mayzent, Fox agreed, is likely to be expensive. The therapy is reported to carry a U.S. list price of $88,500 a year. “I always have a concern about the cost of these drugs. They're all fearfully expensive,” he said, noting he treats SPMS patients. His focus now is on working to ensure that possible regulatory and financial hurdles won’t pose too much of an obstacle for patients, especially those with SPMS. “I don't know what the insurance companies are going to do with this, but I'm hoping that it is available for my patients, and I say that as their clinician,” Fox concluded.

High vitamin D levels predict better cognitive function, while smoking is associated with worse long-term cognitive disability in patients with clinically isolated syndrome (CIS), a study suggests. Data from the study was presented by Marianna Cortese, MD, PhD, from the Department of Nutrition, Harvard T.H. Chan…

Smoking and low levels of vitamin D can worsen prognosis for people with clinically isolated syndrome (CIS), researchers who developed a model for predicting long-term disability progression report. Their study, “Predicting the course of CIS patients adding…

Lesions in the infratentorial region of the brain at the onset of clinically isolated syndrome (CIS) and lesions in white matter one year after CIS onset are associated with worse disability 30 years later, a study reports. The study, “Early MRI predictors of long-term multiple sclerosis outcomes:…

Poor sleep quality is very common among patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS), and is associated with a lower quality of life, and greater fatigue, depression and anxiety, according to a real-world study in patients treated with Betaferon (interferon beta-1b). The study, “…

Higher-than-usual levels of specific antibodies in the blood of patients with clinically isolated syndrome (CIS) may predict a faster progression to multiple sclerosis (MS), an Australian study reports. The specific antibody is known as IgG3, an immunoglobulin known to promote inflammation. The study, “Higher Serum Immunoglobulin G3 Levels May Predict…

Changes in the brains of patients with clinically isolated syndrome (CIS), the first clinical presentation of multiple sclerosis (MS), may be partly responsible for depressive symptoms and reduced quality of life in these patients, a study shows. The study with that finding, “Health-related quality of life, neuropsychiatric…

Cerebrospinal fluid levels of neurofilament light chain, a protein associated with nerve cell damage, can predict disease progression in people with clinical isolated syndrome (CIS) and relapsing-remitting multiple sclerosis (RRMS), a Swedish study found. Higher levels…

B-cell alterations in peripheral blood may predict the conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS), a recent study suggests. Conducted in Turkey, the study, “Peripheral blood memory B cell frequency predicts conversion from clinically isolated syndrome to multiple sclerosis,” was published in…

Eating a diet high in salt won’t worsen or speed up multiple sclerosis (MS) symptoms, concludes a study of MS patients with clinically isolated syndrome (CIS). That contradicts earlier studies by researchers from Argentina, Vermont and elsewhere who warned of a possible link between high sodium consumption and MS. The…

A common acne medicine called minocycline can reduce the rate of multiple sclerosis progression in patients who are at early stages of the disease, according to a Phase 3 clinical trial. The finding was from the MinoCIS trial (NCT00666887) of minocycline, which goes by the brand name Mynocan and other…

(Editor’s note: Tamara Sellman continues her occasional series on the MS alphabet with this second of three parts on terms starting with the letter “C.”) When it comes to multiple sclerosis, mastering an understanding of the disease means you need to mind your Ps and Qs, dot your Is, cross your Ts,…

  When thinking about multiple sclerosis (MS), it’s important to remember there are four distinct types of the disease. Most of you well know this, so I’ll just mention them here: relapsing-remitting MS (RRMS); secondary progressive MS; primary progressive MS, and clinically isolated syndrome. (Anyone needing or wishing more information…

A long-term study underscores the potential benefits, especially in terms of relapses, of multiple sclerosis (MS) patients beginning treatment as soon as possible after symptoms appear — even before the disease is definitely diagnosed. “The 11-year long-term follow-up study from the randomized BENEFIT CIS trial” was published in the journal Neurology. Researchers in…

The Russian Ministry of Health recently granted Marketing Authorization (ЛП-003567) to R-Pharm JSC for the development of  “Glatirat” (Glatiramer acetate), a drug intended for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome. According to a press release, the registration of “Glatirat” was based…

A team of researchers suggested that cigarette smoking is associated with adverse effects to white matter in the brain, and reported that smoking may underlie the clinical course of clinically isolated syndrome, an early and potentially predictive symptom of a progression to multiple sclerosis (MS). The study, “Influence of cigarette smoking on white matter in patients with…

Researchers are continuing to make headway in discovering new insights into how MS works, which in turn could lead to next-generation therapies. A new study shows that in the early stages of multiple sclerosis (MS), plasma micro particles act as biomarkers as well as pathological factors that induce endothelial permeability and…