Pathogenesis
Is Epstein-Barr virus infection not a prerequisite for MS?
Critical disparities in the diagnostic timeline of MS quantified
New therapies and applications
Novel monoclonal antibody obexelimab demonstrates efficacy in phase 2 trial
GLP-1RAs are safe for MS patients but do not alter disease course
Remyelination
No remyelinating effects of bazedoxifene in postmenopausal MS patients
Follow-up data and subgroup analyses
NEDA sustained for up to 10 years with ocrelizumab in treatment-naïve RMS
New findings support ofatumumab as first-line therapy in early MS
Cladribine is associated with stable or improved cognition over 4 years in RMS
Progressive MS
Tolebrutinib is not effective in PPMS in the PERSEUS trial
Fenebrutinib is non-inferior to ocrelizumab in PPMS
NMOSD
Daratumumab is a promising novel treatment for NMOSD
Daratumumab, a humanised monoclonal antibody targeting the CD38 glicoprotein, reduced the risk of relapse in patients with aquaporin-4 immunoglobulin G (AQP4-IgG) positive neuromyelitis optica spectrum disorder (NMOSD) in the phase 3 DAWN-trial.
“You may ask yourself: neuromyelitis optica, did we not already solve that problem?” asked Prof. Michael Levy (Massachusetts General Hospital, MA, USA) [1]. New therapies with novel mechanisms of action are therefore needed to address these failure rates and safety concerns associated with long-term B-cell depletion.
Daratumumab is a first-in-class humanised monoclonal antibody targeting CD38, representing a novel therapeutic approach in NMOSD. The DAWN study (NCT05403138) was a prospective, double-blind, randomised, parallel-group, phase 3 trial evaluating the safety and efficacy of daratumumab in patients with AQP4-IgG-positive NMOSD. The 135 enrolled participants had experienced at least 1 relapse in the past year or at least 2 relapses in the past 2 years. They were randomised 2:1 to daratumumab (n=90) or placebo (n=45), administered intravenously at 8 mg/kg for 2 weeks, followed by 4 mg/kg doses every 4 weeks thereafter. The primary endpoint was time to first relapse after 48 weeks.
The relapse risk was 74% lower in the daratumumab group than in the control group (HR 0.26; 95% CI 0.14–0.48), which Prof. Levy noted fell within the efficacy range of other approved NMOSD treatments. The on-trial annualised relapse rate (ARR) decreased from 1.0 at baseline to 0.13 in the
daratumumab group, and from 0.9 to 0.51 in the placebo group. EDSS worsening occurred in 5 patients (6%) in the daratumumab group versus 16 (36%) in the placebo group. Notably, some patients in the daratumumab group who did not relapse showed improved neurological function rather than remaining stable.
Daratumumab was well tolerated, with no unexpected safety signals. Hypogammaglobulinaemia was observed, but without a significant increase in infection rates. The authors concluded that the enhanced selectivity for antibody-generating plasmablasts and plasma cells, rather than pan-B lymphocytes, may prove safer and more suitable for long-term maintenance therapy in NMOSD.
- Zhang C, et al. Anti-CD38 mAb daratumumab in neuromyelitis optica spectrum disorders (DAWN): A multicenter, randomized, double-blind, placebo-controlled phase III trial. LB1.2, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
Copyright ©2026 Medicom Education B.V.
In the randomised phase 3 FENtrepid trial, fenebrutinib was non-inferior to ocrelizumab at reducing the risk of disability progression in patients with primary progressive MS (PPMS). The oral Bruton tyrosine kinase inhibitor (BTKi) fenebrutinib significantly slowed disability progression [1].
Fenebrutinib is an oral, highly selective, non-covalent, reversible BTKi that penetrates the central nervous system. In the phase 2 trial FENopta (NCT05119569), it rapidly reduced acute inflammatory activity in relapsing MS [2]. The FENtrepid trial (NCT04544449) evaluated the efficacy and safety of fenebrutinib in adult patients with PPMS. Prof. Amit Bar-Or (University of Pennsylvania, PA, USA) noted that a “bold” decision was taken to compare fenebrutinib head-to-head with ocrelizumab, which remains the only approved therapy for PPMS.
FENtrepid was designed as a phase 3, multicentre, randomised, double-blind, double-dummy, parallel-group study. The composite primary endpoint was 12-week confirmed disability progression (cCDP-12), defined as an increase in the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25-FW), and/or 9-Hole Peg Test (9-HPT).
A total of 985 patients with PPMS were randomised 1:1 to receive either oral fenebrutinib 200 mg twice daily plus placebo infusions, or intravenous ocrelizumab 600 mg plus oral placebo every 24 weeks. The mean age at baseline was 48.9 years (SD 10.3).
The median baseline EDSS score was 5.0; the mean duration since MS symptom onset and diagnosis was 9.0 and 4.7 years, respectively. The trial achieved its primary goal of demonstrating non-inferiority of fenebrutinib versus ocrelizumab at delaying cCDP-12. cCDP-12 occurred in 58.8% of patients in the fenebrutinib group versus 66.1% in the ocrelizumab group, representing a relative risk reduction of 12%. As this trial was not powered to detect superiority, this difference was not statistically significant. The strongest treatment effect of fenebrutinib was observed on the 9-HPT component. Treatment effects were consistent across subgroups. The rate of serious adverse events was similar between groups: 19.1% with fenebrutinib versus 18.9% with ocrelizumab. In the fenebrutinib arm, a higher incidence of liver enzyme elevations was observed, as well as a higher number of fatalities (7 versus 1); none of the fatalities was considered related to the study drug.
Prof. Bar-Or added that fenebrutinib reduced the risk of a combined endpoint comprising EDSS and 9-HPT only by 22%. “Had this been the primary endpoint, fenebrutinib would have demonstrated superiority over ocrelizumab.” He also observed that fenebrutinib showed greater relative benefits in patients with non-relapsing progressive disease.
- Bar-Or A, et al. Efficacy and safety of fenebrutinib vs ocrelizumab in primary progressive multiple sclerosis: Primary results of the phase III FENtrepid study. LB1.5, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Bar-Or A, et al. Lancet Neurol. 2025;24(8):656-666.
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In the phase 3 PERSEUS trial, tolebrutinib did not meet the primary endpoint of time to onset of composite confirmed disability progression (cCDP) after 6 months. No significant differences compared with placebo were observed in any of the secondary disability endpoints. Safety findings were consistent with those from previous phase 3 trials of tolebrutinib.
Tolebrutinib is an oral, brain-penetrant, and bioactive Bruton tyrosine kinase inhibitor (BTKi). Dr Robert Fox (Cleveland Clinic, OH, USA) presented the main results from the PERSEUS trial (NCT04458051), evaluating the efficacy and safety of tolebrutinib in primary progressive MS (PPMS) [1]. The 767 participants were aged 18–55 years, had an Expanded Disability Status Scale (EDSS) score of 2.0–6.5, positive cerebrospinal fluid findings, and could not or would not use ocrelizumab. Participants were randomised 2:1 to once-daily oral tolebrutinib 60 mg (n=515) or placebo (n=252). The composite primary endpoint was sustained increase over ≥6 months in EDSS (by ≥1 point for a baseline score of ≤5.5, or by ≥0.5 points with a score of >5.5), Timed 25-Foot Walk (T25-FW) by ≥20%, and/or 9-Hole Peg Test (9-HPT) by ≥20%.
The mean age was 45.3 years, and the mean time since PPMS diagnosis was 4.2 years. At baseline, the mean EDSS was 4.9, 59% of participants were treatment-naïve, and 89% had no gadolinium-enhancing (Gd+) lesions on MRI. In total, 588 patients completed the trial: 398 (77.3%) in the tolebrutinib group and 190 (75.4%) in the placebo group.
Tolebrutinib did not differ from the placebo on the primary endpoint, with a cumulative incidence of cCDP of 66% versus 61%, respectively (HR 1.01; 95% CI 0.81–1.26; P=0.94). Over half of the composite events were driven by the T25-FW component (59% and 55%, respectively). For the secondary endpoint of time to 6-month confirmed disability progression (CDP), Dr Fox noted a non-significant trend favouring tolebrutinib. Tolebrutinib was associated with fewer new or enlarging T2-lesions, with an adjusted rate ratio of 0.54 versus placebo (95% CI 0.35–0.83; P=0.005), and with less brain volume loss after 4 years (P=0.01). The general adverse event profile, including the risk of drug-induced liver injury, was consistent with previous tolebrutinib studies.
“Disability accumulation observed in this PERSEUS PPMS population appears to be less impacted by tolebrutinib than seen in other trials of this BTK inhibitor,” Dr Fox concluded. He highlighted the key differences between PERSEUS and the phase 3 ORATORIO trial of ocrelizumab in PPMS [2]. Fewer participants in PERSEUS had Gd+ T1 lesions at baseline, and a higher proportion had been previously treated.
- Reich DS, et al. Efficacy and safety of tolebrutinib versus placebo in primary progressive multiple sclerosis: Results from the phase 3 PERSEUS trial. LB1.4, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Montalban X, et al. N Engl J Med. 2017;376(3):209-20.
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A pooled analysis of data from the extension of the CLARIFY-MS and MAGNIFY-MS studies assessed the long-term effects of cladribine on cognitive function in patients with relapsing MS (RMS). Results showed that most participants had stable or improved cognitive function, with clinically meaningful improvements or stability in cognitive processing speed (CPS) observed over 4 years [1].
Cognitive decline is a highly prevalent and debilitating symptom of MS, often present even at early stages of the disease. The CLARIFY-MS (NCT03369665) and MAGNIFY-MS (NCT03364036) studies showed that short-course cladribine tablets can stabilise or improve cognitive function for up to 4 years, as measured by the Symbol Digit Modalities Test (SDMT) [2,3]. The pooled analysis included data from 499 patients: 280 participating in the CLARIFY-MS extension (NCT00641537) and 219 in the MAGNIFY-MS extension (NCT04783935). All participants received short-course cladribine (cumulative dose of 3.5 mg/kg) in years 1 and 2, followed by a treatment-free period in years 3 and 4.
At baseline, the mean age was 37.9 years, 68.7% were women, and the median SDMT was 53 points. After 48 months, the least-squares mean SDMT scores improved by 1.79 points (95% CI 1.05–2.54; P<0.0001) in the total population and by 2.22 points (95% CI 1.40–3.04; P<0.0001) in patients aged <50 years (n=434). SDMT in patients aged ≥50 years (n=65) improved by 0.81 points (95% CI -4.97 to 6.59; P=0.7806), which was not statistically significant.
Most participants had stable or improved SDMT scores after 48 months. Using a threshold of a ≥4-point change, 74.4% were stable or improved, and 25.2% worsened. A ≥8-point change threshold yielded proportions of 86.6% and 12.9%, respectively. Percentages of stable or improved patients were relatively high among patients aged ≥50 years and among those with low (<53) versus high (≥53) baseline SDMT scores.
Based on these findings, the authors suggested that cladribine tablets have long-term benefits beyond their effects on conventional disability measures, particularly when initiated at an early stage of MS. This complementary effect, the authors noted, supports early use to maximise benefit.
- Brochet B, et al. Cladribine tablets maintain or improve cognition over 4 years in people with relapsing multiple sclerosis: Pooled analyses of the CLARIFY-MS and MAGNIFY-MS Extension Studies. P117, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Selmaj K, et al. Sustained disease-activity-free (NEDA) status in patients with relapsing multiple sclerosis (RMS) treated with cladribine tablets: data from the CLARITY extension study. P846, ECTRIMS Congress 2024, 18–20 September, Copenhagen, Denmark.
- De Stefano N, et al. Long-term effectiveness of cladribine tablets over 4 years in relapsing multiple sclerosis: Results from the MAGNIFY-MS Extension study. P349, ECTRIMS Congress 2024, 18–20 September, Copenhagen, Denmark.
Copyright ©2026 Medicom Education B.V.
A post-hoc analysis of the ASCLEPIOS I/II trials comparing ofatumumab with teriflunomide focused on newly diagnosed relapsing MS (RMS) patients with low disease activity. In this subgroup, ofatumumab was associated with >2-fold higher odds of remaining free of disease activity at 1 year and an 18-fold higher odds at 2 years [1].
The rationale for this post-hoc analysis was the well-documented evidence that early use of high-efficacy therapy is associated with less accrual of long-term disability [2–4]. In the phase 3 ASCLEPIOS I/II trials (NCT02792218/NCT02792231), the anti-CD20 monoclonal antibody ofatumumab demonstrated a favourable safety and superior efficacy versus teriflunomide in the overall RMS population, as well as in the recently diagnosed (≤3 years) and treatment-naïve subgroups [5,6]. Prof. Heinz Wiendl (University of Freiburg, Germany) presented the results from a subgroup analysis of 261 treatment-naïve patients with early MS and low disease activity, defined as no more than 1 relapse in the 2 years prior to enrolment. The primary efficacy endpoint was no evidence of disease activity (NEDA-3).
In year 1, the proportions achieving NEDA-3 were 43.9% with ofatumumab versus 28.9% with teriflunomide (OR 2.38). In year 2, these proportions were 89.9% versus 34.4%, respectively (OR 18.27).
Despite the low clinical disease activity, ofatumumab demonstrated a pronounced effect on MRI activity and neurofilament light (NfL) levels, and a trend toward a lower annualised relapse rate (ARR):
- Adjusted number of gadolinium-enhancing (Gd+) T1 lesions: 0.02 versus 0.30 (RR 0.08; 95% CI 0.03–0.21; P<0.001).
- Adjusted number of new or newly enlarging T2 lesions: 0.62 versus 3.59 (RR 0.17; 95% CI 0.12–0.26; P<0.001).
- ARR: 0.07 versus 0.10 (RR 0.63; 95% CI 0.32–1.26; P=0.192).
- Serum NfL levels: a relative reduction with ofatumumab of 20.4% in year 1 (P=0.258) and 15.2% in year 2 (P<0.001).
The safety of ofatumumab was consistent with that observed in the overall ASCLEPIOS I/II population. Adverse events occurred in 86.7% of patients in the ofatumumab group and 88.7% in the teriflunomide group. Rates of serious adverse events and serious infections were similar between groups (5.8% versus 7.1%).
Prof. Wiendl and colleagues concluded that these findings support the early use of ofatumumab as first-line therapy in RMS patients, even in the presence of low disease activity.
- Wiendl H, et al. Efficacy and safety of ofatumumab in treatment-naive people with early RMS and low clinical disease activity. P134, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Kappos L, et al. JAMA Neurol. 2020;77(9):1132–1140.
- Lublin FD, et al. Brain. 2022;145(9):3147–3161.
- He A, et al. Lancet Neurol. 2020;19(4):307–316.
- Hauser SL, et al. N Engl J Med. 2020;383(6):546–557.
- Gärtner J, et al. Mult Scler. 2022;28(10):1562–1575.
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In approximately 9 of 10 treatment-naïve (TN) patients with relapsing MS (RMS) treated with ocrelizumab, either intravenous (IV) or subcutaneous (SC), no evidence of disease activity (NEDA-3) was maintained in any given year. Long-term safety data were reassuring, with infection rates decreasing over time and serious infection rates remaining low and stable [1].
These findings derive from long-term follow-up of the phase 3 OPERA I/II (NCT01247324/NCT01412333) [2], with up to 10 years of follow-up, and the phase 3 OCARINA II study (NCT05232825) [3], with 2 years of follow-up. Both studies enrolled TN patients with early RMS. In OPERA I/II, 603 participants were randomised to IV ocrelizumab, of whom 375 had been diagnosed with MS within the previous 2 years. In OCARINA II, 46 participants were randomised to SC ocrelizumab.
The primary efficacy endpoint was NEDA-3, defined as the absence of protocol-defined relapses, no 48-week confirmed disability progression (CDP48), and no MRI activity (no gadolinium-enhancing T1 lesions (Gd+ T1) and no new or enlarging T2 lesions. Event rates over the entire study period and safety were also evaluated.
Across both studies, approximately 9 of 10 participants achieved NEDA-3 in any given year. Efficacy appeared comparable between IV and SC formulations. Most participants remained free of relapses, CDP48, and MRI activity throughout the ocrelizumab treatment.
Over the entire follow-up period, corresponding to 4,547.8 patient-years in the IV group (10 years) and 95.8 patient-years in the SC group (2 years), the proportions of patients achieving key outcomes were as follows:
- NEDA-3: 60.9% (IV) and 90.6% (SC);
- No relapse: 75.0% (IV) and 97.8% (SC);
- No CDP48: 83.4% (IV) and 98.1% (SC);
- No Gd+ T1 lesions: 97.8% (IV) and 98.6% (SC);
- No new or enlarging T2 lesions: 89.2% (IV) and 89.5% (SC).
Regarding safety, infection rates declined over time, while serious infections remained low and stable in both groups. In the IV group, infection rates per 100 patient-years were 90.5 at year 1, 68.0 at year 5, and 44.1 at year 10. Corresponding rates of serious infections were 0.68, 1.72 and 1.3 per 100 patient-years, respectively. In the SC group, infection rates decreased from 83.1 per 100 patient-years at year 1 to 38.0 at year 3; no serious infections were reported in this cohort.
Overall, these long-term data support sustained high efficacy and favourable safety profile of both IV and SC ocrelizumab in treatment-naïve patients with early RMS.
- Newsome SD, et al. No Evidence of Disease Activity in treatment-naive people with relapsing multiple sclerosis treated with intravenous or subcutaneous ocrelizumab: Findings of the OPERA (10 Years) and OCARINA II (2 Years) studies. P125, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Hauser SL, et al. N Engl J Med. 2017;376(3):221-234.
- Newsome SD, et al. Neurology. 2025;104(9):e213574.
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In the placebo-controlled phase 2 ReWRap trial, bazedoxifene failed to demonstrate remyelinating effects in postmenopausal women with relapsing MS (RMS). The treatment was well tolerated, but no primary or secondary endpoints were met. Nonetheless, the findings provide important insights for the design of future remyelinating trials.
Therapeutic strategies capable of slowing down or potentially reversing immune-mediated demyelination in MS remain a major unmet need in MS. Dr Riley Bove (University of California San Francisco, CA, USA) noted that most remyelination trials in MS have raised more questions than answers, particularly regarding optimal molecule selection, target population, study design, and outcome measures [1]. “Two molecules have demonstrated a signal consistent with remyelination: clemastine [2] and bexarotene [3]. There is a need for more remyelinating treatments that are tolerable and have different mechanisms of action.”
Bazedoxifene, a selective oestrogen receptor modulator (SERM), was investigated as a candidate remyelinating therapy. Given its regulatory approval for postmenopausal osteoporosis, postmenopausal women with MS were selected as the target population.
ReWRap (NCT04002934) was a double-blind phase 2 trial enrolling ambulatory women aged 45–60 years (>40 if postmenopausal) with RMS of less than 25 years’ duration and an Expanded Disability Status Scale (EDSS) score of 0–6. Participants were randomised to either 6 months of bazedoxifene 40 mg daily (early-start group; n=33) or 3 months of placebo followed by 3 months of bazedoxifene (delayed-start group; n=33). The primary endpoint was the change in myelin water fraction (MWF) within the corpus callosum on MRI, a quantitative biomarker of myelin content.
No significant between-group differences in MWF were observed at 3 or 6 months. Similarly, changes in the Multiple Sclerosis Functional Composite (MSFC) score did not differ between groups. Study retention and completion rates were high (91.3%). No clinical relapses or new gadolinium-enhancing (Gd+) T2 lesions were recorded during the study period. Adverse events were comparable between groups, and no severe adverse events were reported.
In retrospect, Dr Bove suggested that future studies of SERMs in MS might consider enrolling younger patients (e.g., 45–50 years) and limiting treatment duration to 1 year. She also proposed that combining bazedoxifene with metformin could enhance remyelination by promoting responsiveness of oligodendrocyte precursor cells (OPCs).
- Bove R, et al. ReWrap: A phase II delayed start myelin repair RCT. LB1.1, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.
- Green AJ, et al. Lancet. 2017;390(10111):2481-2489.
- Brown WL, et al. Lancet Neurol. 2021;20(9):709-720.
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