The quest to understand and slow disease progression in multiple sclerosis (MS) continued in 2024, with research revealing possible new treatments and furthering knowledge about the disease course.
Highly effective disease-modifying therapies (DMTs) have succeeded in reducing MS relapses, but when relapses are prevented, progression independent of relapse activity (PIRA) is uncovered, noted Stephen Hauser, MD, of the University of California San Francisco, in an published early this year.
This progression was previously obscured by fluctuating neurologic findings due to relapses and partial remissions, he pointed out. "Thus, progression is present in most, if not all, patients with multiple sclerosis, regardless of where they are in the disease continuum," he wrote.
The Science of MS
The year started with a report in Nature that detailed how genetic risk for MS was brought into Europe by sheep and cattle herders migrating from the east approximately 5,000 years ago. These variants likely protected livestock herders against pathogens from their domesticated animals in the past, but in a modern environment they raised the risk of MS. "The risk genes are now miscast in terms of their original biological role," said Lars Fugger, MD, PhD, of Oxford University in England.
Also early in 2024, researchers uncovered a specific autoantibody signature that was evident in some MS patients 5 years before clinical symptoms appeared. The autoantibodies, which appeared to bind to both human cells and common pathogens, were associated with higher levels of serum neurofilament light (NfL) and may help identify those patients with clinically isolated or radiologically isolated syndromes who might develop MS.
Data throughout the year continued to suggest that blood biomarkers at disease onset may be tied to future disease worsening. In an observational study, serum NfL predicted both relapse-associated worsening and PIRA. In patients who had low NfL levels, serum levels of glial fibrillary acidic protein (GFAP) correlated with PIRA.
As knowledge about MS evolved, so did recommendations for revised diagnostic criteria. An upcoming version of the McDonald criteria will include new biomarkers to help diagnose MS earlier, the Advisory Committee on Clinical Trials in Multiple Sclerosis said.
These revisions signal a shift toward looking at MS more as a biologically based disease, the committee noted, similar to diagnostic changes proposed in Alzheimer's and Parkinson's disease. The new McDonald criteria also will allow MS to be diagnosed in some asymptomatic individuals previously classified as having radiologically isolated syndrome.
Investigational Treatments
In February, phase II trial data showed that frexalimab, an investigational second-generation CD40 ligand inhibitor, led to fewer new gadolinium-enhancing T1-weighted lesions in relapsing MS.
At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 in MS patients who received 1,200 mg of frexalimab intravenously and 0.3 in those who received 300 mg of frexalimab subcutaneously, compared with 1.4 in those who received placebo. Secondary imaging endpoints generally were in the same direction as the primary endpoint. Plasma levels of NfL appeared to decrease in the frexalimab groups.
At two international meetings -- the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) forum in March, and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in September -- research shed light on the possible roles that investigational Bruton's tyrosine kinase (BTK) inhibitors might play in MS.
At ACTRIMS, the BTK inhibitor tolebrutinib failed to eliminate paramagnetic rim lesions in a small phase IIa study of active MS. And a pair of phase III studies at ACTRIMS showed that treatment with evobrutinib led to similar annualized relapse rates at 12 weeks compared with teriflunomide (Aubagio). Evobrutinib did not surpass teriflunomide in secondary outcomes, including serum NfL concentrations, numbers of new gadolinium-enhancing lesions, or numbers of new or enlarging T2 lesions.
But tolebrutinib showed something novel at ECTRIMS. In the phase III HERCULES trial, tolebrutinib slowed confirmed disability progression (CDP) in people with non-relapsing secondary progressive MS, making it the first drug to do so. The 6-month CDP was 26.9% in the tolebrutinib group and 37.2% in the placebo group (P=0.0026).
"We have over 20 approved MS therapies," said HERCULES researcher Robert Fox, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio. "They're all focused on the relapsing component. We don't have any therapies with demonstrated efficacy in non-relapsing secondary progressive MS."
High-Efficacy DMTs
Research contributed to ongoing debates about when highly effective DMTs should be started or stopped. In a retrospective study of 530 patients with pediatric-onset MS, starting treatment with highly effective DMTs was associated with a 54% lower risk of first relapse over 5 years, compared with moderately effective therapies.
Moreover, high-efficacy monoclonal antibody therapy -- ocrelizumab (Ocrevus), rituximab (Rituxan), or natalizumab (Tysabri) -- started during childhood reduced long-term disability in pediatric-onset MS, registry data suggested. At ages 23-27, those who started treatment as adolescents (at ages 12-17) had less disability than those who started at ages 20-22.
At the other end of the age spectrum -- at ages 50 and older -- data showed that stopping high-efficacy therapy in patients with non-active MS led to higher relapse risks compared with maintaining treatment. Discontinuing natalizumab or fingolimod (Gilenya) carried the highest risks.
In France, an analysis of registry data revealed that women with relapsing MS were less likely to get high-efficacy DMTs than men. Treatment decisions may have been influenced by a desire to become pregnant, the researchers suggested. The use of high-efficacy DMTs is frequently limited by potential and unknown risks associated with pregnancy, and there's often insufficient data available when these drugs first come to market, they added.
Other New Research
Other research in MS this year included:
Some Cancers Occur More Frequently in Multiple Sclerosis Patients
Higher Comorbidity Burden in Multiple Sclerosis Tied to Worse Outcomes
Intermittent Fasting Shows Promise in Multiple Sclerosis
Study Suggests No Overall Increased Risk of MS Relapse After COVID Boosters
Novel Drug Made of Gold Nanocrystals Appears Safe in Multiple Sclerosis
Ocrelizumab Trial Fills Research Gap for Black, Hispanic MS Patients
Breastfeeding While Taking MS Monoclonal Antibody Drugs Appears Safe
Cognitive Decline in MS Predicted by Paramagnetic Rim Lesions
Ozanimod Controls MS Disease Activity Regardless of Age
Long COVID May Be Difficult to Identify in MS
Obesity Associated With Faster MS Disease Progression
Sophie Putka contributed to this report.