2026 American Academy of Neurology Abstract Website

Cristina Granziera¹, Patrick Vermersch², Biljana Djukic³, Svend S. Geertsen³, Andrea T. Shafer³, Philippe Truffinet⁴, Gavin Giovannoni⁵
¹Translational 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, ²University of Lille, Inserm U1172, Lille Neuroscience and Cognition, CHU Lille, FHU Precise, Lille, France, ³Sanofi, Cambridge, MA, USA, ⁴Sanofi, Gentilly, France, ⁵Queen Mary University of London, London, UK

Objective:

To report frexalimab’s treatment effects on plasma levels of neurofilament light chain (NfL), chemokine (C-X-C motif) ligand 13 (CXCL13), and brain volume loss (BVL) at year 3 (Week [W] 144) of the phase 2 open-label extension (OLE).

Background:

Frexalimab, a second-generation anti-CD40L monoclonal antibody, inhibits the costimulatory CD40/CD40L pathway, and may recalibrate immune networks involving adaptive and innate immunity. In the double-blind period of the phase 2 trial (NCT04879628) in participants with relapsing multiple sclerosis (pwRMS), frexalimab-1200mg/intravenous (IV) showed an 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions vs placebo at W12. This was accompanied by 24% and 21% reductions in plasma NfL and CXCL13 levels, respectively.

Design/Methods:

129 pwRMS were randomized (4:4:1:1) to frexalimab-1200mg/IV every-4-weeks (q4w), frexalimab-300mg/subcutaneous (SC) q2w, or matching placebo. After W12, placebo recipients switched to frexalimab and entered OLE. The SC dose was increased to 1800mg-q4w to achieve pharmacokinetic comparability with the 1200mg-q4w IV dose. Plasma NfL and CXCL13 (baseline−W144) were measured by Quanterix Simoa® assay and Meso Scale Discovery assay, respectively. BVL (baseline−W144) was estimated using Jacobian integration. Results are summarized as % change of geometric mean from baseline for plasma NfL and CXCL13, and median % change from baseline for BVL.

Results:

From baseline to W144, frexalimab treatment reduced the plasma NfL levels by 47% (IV), 49% (SC), 35% (placebo»IV), and 45% (placebo»SC). CXCL13 levels decreased by 48%, 61%, 34%, and 28%, respectively. In the IV arm (Phase 3 dose), BVL from baseline was -0.84% (IQR: -1.14 to -0.50) for whole brain, -1.18% (-1.85 to -0.13) for thalamus, and -0.85% (-1.67 to -0.39) for cerebral cortex.

Conclusions:

Three years of f rexalimab treatment demonstrated marked reductions in NfL and CXCL13, and limited BVL in pwRMS. These data contribute to understanding the effect of frexalimab on neuroinflammation and neurodegeneration, and support further investigations in both RMS and non-relapsing secondary progressive MS.