2025 American Academy of Neurology Abstract Website

Patrick Vermersch¹, Cristina Granziera², Yang Mao-Draayer³, Gary Cutter⁴, Oleksandr Kalbus⁵, Ivan Staikov⁶, Michal Dufek⁷, Xavier Montalban⁸, Stephen Krieger⁹, Stephane Saubadu¹⁰, Xiaodong Luo¹¹, Brendan Smyth¹¹, Biljana Djukic¹², Philippe Truffinet¹⁰, Erik Wallstroem¹², Gavin Giovannoni¹³
¹University of Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, France, ²Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine; Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland, ³Autoimmunity Center of Excellence, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA, ⁴Department of Biostatistics, UAB School of Public Health, Birmingham, AL, USA, ⁵Department of Neurology, Dnipro State Medical University, Dnipro, Ukraine, ⁶Clinic of Neurology and Sleep Medicine, Acibadem City Clinic University Hospital Tokuda, Sofia, Bulgaria, ⁷First Department of Neurology, St. Anne’s University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic, ⁸Multiple Sclerosis Centre of Catalonia, Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain, ⁹Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, USA, ¹⁰Sanofi, Gentilly, France, ¹¹Sanofi, Bridgewater, NJ, USA, ¹²Sanofi, Cambridge, MA, USA, ¹³Queen Mary University of London, London, United Kingdom

Objective:

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).

Background:

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.

Design/Methods:

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]).

Results:

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/IVthrough 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.

Conclusions:

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.