Late-breaking research at ACTRIMS Forum 2026: Advances and challenges in MS

Presented by Dr Riley Bove, the late breaking trial did not meet its primary or secondary remyelination endpoints in women with relapsing multiple sclerosis, but it demonstrated excellent retention and tolerability, with no severe adverse events, relapses or new MRI lesions observed.

Numerical trends favouring early treatment were noted for imaging and functional outcomes, including in a subgroup with chronic optic neuropathy. Investigators emphasized the importance of learning from negative trials in remyelination research and highlighted the potential role of novel digital endpoints and revised sample size calculations in future studies.

Dr Riley Bove stated, “From a safety and tolerability standpoint, we we’re very encouraged”, “From an efficacy standpoint, when we looked at our main trial outcome, which was effect on myelin water fraction, we did not see any statical improvement.”²

Targeting plasma cells in NMOSD: the DAWN trial

In neuromyelitis optica spectrum disorders (NMOSD), the DAWN Phase III trial is evaluating daratumumab, an anti-CD38 monoclonal antibody, in patients with aquaporin-4 antibody-positive disease. By targeting antibody-secreting plasma cells rather than pan-B-cell depletion, the study seeks to refine therapeutic approaches in NMOSD.³

The results were presented by Dr Michael Levy, and highlighted while efficacy outcomes remain pending, enrolment of 135 patients and completion of treatment without deaths were reported. The trial’s design incorporates comprehensive immunological, imaging and clinical endpoints, and results expected in November 2025 may clarify the role of plasma-cell-directed therapies in relapse prevention among AQP4-IgG positive NMOSD patients.

Obexelimab demonstrates strong MRI efficacy in relapsing MS

Presented by Dr Amit Bar-Or, week 12 results from the MoonStone Phase II trial provided the first clinical evidence of activity for obexelimab, a bifunctional antibody that co-engages CD19 and the inhibitory FcγRIIb receptor to suppress B-cell activation without depletion.⁴

Obexelimab achieved a near-complete suppression of new gadolinium-enhancing T1 lesions compared with placebo, alongside significant reductions in new or enlarging T2 lesions. These findings suggest that non-depleting B-cell inhibition may offer an alternative immunomodulatory strategy in relapsing MS, with a safety profile consistent with prior studies. Longer-term open-label extension data will be critical to assess durability and clinical impact.

PERSEUS: mixed signals for tolebrutinib in PPMS

Data from the PERSEUS Phase III trial was presented at ACTRIMS 2026, by Dr Robert Fox, the trial evaluated tolebrutinib, an oral, brain-penetrant Bruton’s tyrosine kinase inhibitor, in primary progressive MS (PPMS). Despite encouraging results in other MS phenotypes, the study did not meet its primary endpoint of delaying six-month confirmed disability progression versus placebo. The results did find tolebrutinib to be associated with reduced brain volume loss compared with placebo at 6 months in patients with PPMS.

The trial population was characterized by advanced disease and limited inflammatory activity at baseline, reflecting real-world PPMS. Although detailed efficacy outcomes were pending presentation, the results underscore the ongoing difficulty of demonstrating treatment effects in progressive MS and raise important questions about trial design, patient selection and endpoint sensitivity.

Dr Robert Fox stated “My initial reaction is ‘puzzled,’ because we saw a reduced risk of disability progression with tolebrutinib in HERCULES and GEMINI I/II, so I was expecting to see the same in PERSEUS. So why the difference? For one, the outcome was different: composite progression with PERSEUS rather than Expanded Disability Status Scale (EDSS),” “It was anticipated that composite progression would be more sensitive, but that seems not to have been the case. The additional ‘signal’ from the compositive may have been outweighed by additional ‘noise.“⁵

FENtrepid: fenebrutinib versus ocrelizumab in PPMS

In contrast, the FENtrepid study represents a landmark design in PPMS research, directly comparing fenebrutinib with ocrelizumab, the only approved therapy for the condition. This Phase III trial is the first to use an active comparator in PPMS rather than placebo.⁶

While full efficacy and safety results were awaited at the time of presentation, the study enrolled nearly 1,000 patients and will provide critical evidence on whether CNS-penetrant BTK inhibition can meaningfully impact disability progression relative to established B-cell depletion. The results are anticipated to inform both clinical practice and future progressive MS trial design.

“I was delighted that fenebrutinib indeed emerged as non-inferior to ocrelizumab, and in fact at least nominally appeared to be a little better at limiting progression of disability in PPMS. It’s exciting to imagine a single agent that might have an important impact on both relapsing and progressive biologies of MS,” lead author Amit Bar-Or stated.⁷

Key themes emerging from ACTRIMS 2026

Together, the late-breaking studies presented at ACTRIMS Forum 2026 reflect a field grappling with the biological and methodological challenges of progressive disease while continuing to innovate in immune modulation and repair strategies.

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References

1. Bove R et al. ReWRap: a Phase II delayed-start myelin repair randomised controlled trial in midlife women with MS. Presented at ACTRIMS Forum 2026, 5-7 February 2026, San Diego, CA, USA. Late-Breaking Abstract LB1 973. Available at: https://www.abstractsonline.com/pp8/#!/21408/presentation/973 (accessed 12 Feb 2026).
2. NeurologyLive. Remyelinating drug bazedoxifene fails to meet end points in Phase II study in multiple sclerosis. NeurologyLive. Available at: https://www.neurologylive.com/view/remelyinating-drug-bazedoxifene-fails-meet-end-points-phase-2-study-ms (accessed 12 Feb 2026).
3. Okuda DT et al. Week 12 results from MoonStone, a Phase 2 study of obexelimab in relapsing multiple sclerosis. Presented at ACTRIMS Forum 2026, 5-7 February 2026, San Diego, CA, USA. Late-Breaking Abstract LB1 15. Available at: https://www.abstractsonline.com/pp8/#!/21408/presentation/15 (accessed 12 Feb 2026).
4. Reich DS et al. Efficacy and safety of tolebrutinib versus placebo in primary progressive multiple sclerosis: results from the Phase III PERSEUS trial. Presented at ACTRIMS Forum 2026, 5-7 February 2026, San Diego, CA, USA. Late-Breaking Abstract LB1 972. Available at: https://www.abstractsonline.com/pp8/#!/21408/presentation/972 (accessed 12 Feb 2026).
5. Zhang C et al. Anti-CD38 mAb daratumumab in neuromyelitis optica spectrum disorders (DAWN): a multicentre, randomised, double-blind, placebo-controlled Phase III trial. Presented at ACTRIMS Forum 2026, 5-7 February 2026, San Diego, CA, USA. Late-Breaking Abstract LB1 974. Available at: https://www.abstractsonline.com/pp8/#!/21408/presentation/974 (accessed 12 Feb 2026).
6. Bar-Or A et al. Efficacy and safety of fenebrutinib versus ocrelizumab in primary progressive multiple sclerosis: primary results of the Phase III FENtrepid study. Presented at ACTRIMS Forum 2026, 5-7 February 2026, San Diego, CA, USA. Late-Breaking Abstract LB1 971. Available at: https://www.abstractsonline.com/pp8/#!/21408/presentation/971 (accessed 12 Feb 2026).
7. NeurologyLive. BTK inhibitor fenebrutinib shows noninferiority to ocrelizumab in Phase 3 study in primary progressive MS. Available at: https://www.neurologylive.com/view/btk-inhibitor-fenebrutinib-shows-noninferiority-ocrelizumab-phase-3-study-primary-progressive-ms#:~:text=New%20data%20from%20phase%203,patients%20with%20primary%20progressive%20multiple (accessed 27 Feb 2026).