The year 2024 has seen continued progress in understanding and treating multiple sclerosis (MS), with research uncovering potential new therapies and deepening knowledge of the disease's progression. Studies have ranged from exploring the genetic origins of MS to evaluating the effectiveness of various treatment strategies and identifying biomarkers for early diagnosis and prognosis.
Genetic Origins of MS
Early in the year, a report in Nature detailed how genetic risk for MS was introduced to Europe by sheep and cattle herders migrating from the east approximately 5,000 years ago. According to Lars Fugger, MD, PhD, of Oxford University, these genetic variants, which once protected livestock herders against pathogens from their domesticated animals, now increase the risk of MS in modern environments. "The risk genes are now miscast in terms of their original biological role," Fugger noted.
Early Detection and Biomarkers
Researchers also uncovered a specific autoantibody signature evident in some MS patients 5 years before clinical symptoms appeared. These autoantibodies, which bind to both human cells and common pathogens, were associated with higher levels of serum neurofilament light (NfL) and may help identify individuals with clinically isolated or radiologically isolated syndromes at risk of developing 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 progression independent of relapse activity (PIRA). In patients with low NfL levels, serum levels of glial fibrillary acidic protein (GFAP) correlated with PIRA.
Investigational Treatments
Several investigational treatments for MS have shown promise. In February, phase II trial data indicated that frexalimab, a second-generation CD40 ligand inhibitor, reduced new gadolinium-enhancing T1-weighted lesions in relapsing MS. At week 12, patients receiving 1,200 mg of frexalimab intravenously had an adjusted mean of 0.2 new lesions, while those receiving 300 mg subcutaneously had 0.3 new lesions, compared to 1.4 in the placebo group. Plasma levels of NfL appeared to decrease in the frexalimab groups.
Bruton's tyrosine kinase (BTK) inhibitors are also under investigation. While tolebrutinib failed to eliminate paramagnetic rim lesions in a phase IIa study of active MS, it showed a novel effect in the phase III HERCULES trial. Robert Fox, MD, of the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, reported that tolebrutinib slowed confirmed disability progression (CDP) in people with non-relapsing secondary progressive MS. 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," Fox said. "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
Debates continue regarding when to start or stop highly effective disease-modifying therapies (DMTs). A retrospective study of 530 patients with pediatric-onset MS found that starting treatment with highly effective DMTs was associated with a 54% lower risk of first relapse over 5 years, compared with moderately effective therapies. Furthermore, registry data suggested that high-efficacy monoclonal antibody therapy—ocrelizumab (Ocrevus), rituximab (Rituxan), or natalizumab (Tysabri)—started during childhood reduced long-term disability in pediatric-onset MS. However, data also showed that stopping high-efficacy therapy in patients aged 50 and older with non-active MS led to higher relapse risks compared with maintaining treatment, with discontinuing natalizumab or fingolimod (Gilenya) carrying the highest risks.
Other Notable Findings
Additional research this year has explored various aspects of MS, including the increased frequency of certain cancers in MS patients, the impact of comorbidity burden on outcomes, and the potential benefits of intermittent fasting. Studies have also addressed concerns about COVID-19 boosters and MS relapse risk, as well as the safety of breastfeeding while taking MS monoclonal antibody drugs.
