The following summarizes some of the highlights from Day 2 if the Americas Committee for Treatment and Research in MS (ACTRIMS) Forum 2025.
Effect of ofatumumab on cortical lesions
Update on BTK inhibitors
Emerging concepts in MS: glymphatic system dysfunction
MS risk elevated after EBV+ mononucleosis
Higher discontinuation rate in comorbid MS patients
CONGRESS HIGHLIGHTS – SATURDAY EDITION
Effect of ofatumumab on cortical lesions
The anti-CD20 agent ofatumumab stabilizes cortical demyelination during the first year of therapy, according to an interim analysis of data from a 7T MRI study (Zurawski et al. ACTRIMS 2025;V228). All subjects had cortical lesions (mean 8.1), 38% had thalamic lesions and 81% had leptomeningeal enhancement (LME) at baseline. MRIs were obtained at baseline and after one year of ofatumumab. The cortical lesion burden was generally stable during treatment. The LME foci number was stable in 75% and increased in 25%. LME did not resolve but no subject developed new LME with therapy. There were no relapses or new MRI lesions during treatment. EDSS and T25FW were stable. The study is ongoing.
Update on BTK inhibitors
Tolebrutinib: The phase III HERCULES trial in non-relapsing SPMS reported a significant reduction in 6-month confirmed disability worsening (CDW) with tolebrutinib 60 mg/day vs. placebo although there was no reduction in the rate of brain volume loss (Fox et al. ECTRIMS 2024;O136). In the GEMINI I/II trials in RMS, there was a 29% reduction in 6M CDW but no difference in the annualized relapse rate and a higher number of Gd+ lesions (Oh et al. ECTRIMS 2024;O135). The present post-hoc analysis (n=653) examined whether paramagnetic rim lesions (PRL) were associated with tolebrutinib (Oh et al. ACTRIMS 2025;LB1.1). The risk of 6M CDW was lower in RMS (49% reduction vs. teriflunomide) and non-relapsing SPMS patients (54% reduction vs. placebo) for the subset of patients with ≥4 PRLs at baseline.
Orelabrutinib: Phase II data for orelabrutinib in RRMS have now been reported (Xu et al. ACTRIMS 2025;P094). A total of 158 subjects were randomized to placebo or one of three active dose groups (50 mg/day, 80 mg/day or 50 mg BID) for 12 weeks followed by an open-label extension. All treatment groups demonstrated a significant reduction in the number of new Gd+ T1 and new/enlarging T2 lesions at week 12. The two highest dosing groups also showed a significant reduction in MRI lesions at week 24 vs. placebo/50 mg. There was a 90.4% reduction and a 92.3% reduction in MRI lesions at weeks 12 and 24, respectively, with orelabrutinib 80 mg/day. No serious adverse effects were reported.
Emerging concepts in MS: glymphatic system dysfunction
The glymphatic system was first characterized a decade ago to describe clearance of interstitial fluid and waste products along paravascular drainage pathways (Iliff et al. Sci Transl Med 2012;4:147ra111). Interestingly, deletion of the AQP4 gene impaired the clearance of beta-amyloid, suggesting a link between glymphatic function and neurodegeneration. A new study has speculated that paramagnetic rim lesions (PRLs) may form, in part, due to impaired clearance of iron-containing microglia/macrophages (Tranquille et al. ACTRIMS 2025;P232). The group performed diffusion tensor imaging (DTI) along the perivascular space in 86 MS patients and 23 healthy controls. PRLs, identified with quantitative susceptibility imaging, were categorized as persistent, disappearing or newly-appearing. A DTI index was calculated from NAWM regions as an indicator of glymphatic clearance. Clearance was significantly lower in MS patients compared to healthy controls at baseline. The appearance of new PRLs over five years was significantly associated with lower glymphatic clearance at baseline. No association was found between clearance and the disappearance or persistence of PRLs. Clearance was lower at five-year follow-up among patients with a higher PRL number.
A separate study by the same group also reported that baseline glymphatic clearance was significantly lower in RRMS patients with confirmed disability progression and progression independent of relapse activity (PIRA) at 5- and 10-year follow-up (Tranquille et al. ACTRIMS 2025;P234). No association was seen between glymphatic clearance and CDP/PIRA in patients with progressive MS.
MS risk elevated after EBV+ mononucleosis
A study at the Mayo Clinic, Rochester, Minnesota, conducted a population-based study of the risk of developing MS in individuals with a history of Epstein-Barr virus (EBV)-positive infectious mononucleosis (Diaz-Decaro et al. ACTRIMS 2025;V465). The Rochester Epidemiology Project identified 4721 subjects with EBV+ mononucleosis and compared them to 14,163 controls without EBV infection. The incidence of MS was 2.25 per 10,000 person-years in the EBV+ mononucleosis group after a median of six years compared to 0.77/10,000 PY for the EBV- group after a median of eight years (adjusted hazard ratio 3.03). The aHR for any demyelinating disease was 3.77.
Higher discontinuation rate in comorbid MS patients
A new meta-analysis of 17 studies (N=16,794) has examined the impact of comorbidities on reported adverse events and trial discontinuation (Salter et al. ACTRIMS 2025;CE1.4). The comorbid conditions that were considered included hypertension, hyperlipidemia, diabetes, autoimmunity, cardiovascular/cerebrovascular/peripheral vascular disease, and psychiatric disorders. The overall rate of adverse events of interest was 64%; most were infections. One or more comorbidities was associated with an increasing rate of adverse events. The risk of adverse events was increased 25% in patients with >3 comorbidities, 15% with ≥2 cardiometabolic conditions, and 15% with ≥2 psychiatric conditions. The rate of early discontinuation was also associated with an increasing burden of comorbid conditions. Discontinuations were 23% higher in patients with two comorbid conditions.