Frexalimab, a second-generation anti-CD40L antibody, blocks the CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. In the phase 2 double-blind period (DBP), frexalimab was well-tolerated and efficacious at reducing disease activity, with an 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions with frexalimab_{1200mg/intravenous (IV)} vs placebo at W12.

Report safety and efficacy of frexalimab at Week (W) 96 in the phase 2 (NCT04879628) open-label extension (OLE) in participants with relapsing multiple sclerosis (pwRMS).

129 participants were randomized (4:4:1:1) to frexalimab_1200mg/IV every 4 weeks (q4w) or frexalimab_{300mg/subcutaneous (SC)} q2w or matching placebo. After W12, participants receiving placebo switched to respective frexalimab arms and entered the OLE. During OLE, the SC dose was increased to 1800-mg q4w (frexalimab_1800mg/SC; first high-dose administered on 21-August-2023), resulting in a similar frexalimab exposure as with the 1200-mg q4w IV dose. 36/57 (63%) participants in the SC arms had their W96 magnetic resonance imaging assessments after receiving frexalimab_1800mg/SC. Key endpoints included safety and efficacy outcomes (number of Gd+ T1-lesions, new/enlarging T2-lesions, annualized relapse rate [ARR]).

106 study participants (82%) remained on treatment as of 22-July-2024 (W96 cut-off). At W96, total number of Gd+ T1-lesions (mean [SD]) remained low in participants who continued receiving frexalimab and those who switched from placebo to frexalimab at W12 (IV arms: frexalimab_1200mg/IV: 0.1 [0.5], placebo_IV/frexalimab_1200mg/IV: 0.1 [0.3]; SC arms: 0.4 or below across all groups). New/enlarging T2-lesion monthly count remained low with frexalimab_1200mg/IV through W96. ARR (baseline–W96) was low (0.08 [95% CI, 0.03-0.18]) in frexalimab_1200mg/IV arm; 92% of participants were relapse-free. Frexalimab was well-tolerated through W96. The most common adverse events in the OLE were nasopharyngitis, headache, and COVID-19.

Frexalimab continues to show favorable 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.