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Background/Objectives Frexalimab, a second-generation anti-CD40L antibody, blocks the CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. During the 12-week (W) double-blind period of the phase-2 trial ( NCT04879628) in participants with relapsing multiple sclerosis (pwRMS), frexalimab was well-tolerated and efficacious, with 1200-mg intravenous (IV) arm showing an 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions vs placebo. Here, we report W96 results in the open-label extension (OLE).Methods 129 participants were randomised (4:4:1:1) to frexalimab 1200mg/IV every-4-weeks (q4w) or frexalimab300mg/subcutaneous (SC) q2w or matching placebo. After W12, participants receiving placebo switched to frexalimab arms. During OLE, the SC dose was increased to 1800-mg q4w, resulting in similar frexalimab exposure as with 1200-mg q4w IV dose; 36/57 participants in SC arms received high-dose and underwent W96 MRI assessments. Key endpoints: safety and efficacy (Gd+ T1-lesions, new/enlarging T2-lesions, annualised relapse rate [ARR]).Results 106 participants (82%) remained on treatment at W96. Total number of Gd+ T1-lesions (mean±SD) remained low at W96 in participants who continued receiving frexalimab and who switched from placebo to frexalimab at W12 (IV arms: frexalimab 1200mg/IV: 0.1±0.5, placeboIV/frexalimab1200mg/IV: 0.1±0.3; all SC arms: ≤0.4). New/enlarging T2-lesion monthly count remained low with frexalimab1200mg/IV through W96. ARR (baseline-W96) was low (0.08 [95% CI, 0.03–0.18]) in frexalimab1200mg/IV arm; 92% of participants were relapse-free. Most common adverse events were nasopharyngitis, headache, and COVID-19.Conclusions Frexalimab continues to show favourable safety and sustained reduction in disease activity in pwRMS through W96, supporting its further development in phase-3 trials as a potential high-efficacy, non-lymphocyte-depleting therapy.