Frexalimab is an indirect B cell inhibitor. It block the natural signal that a B cell gets from T cells and antigen presenting cells as it blocks the ligand (binding bit) to the CD40 receptor. This receptor needs to be stumulated at the same time as the antigen receptor for B cells to be activated. Block CD40 ligand and you block CD40 activation. EBV is a sneaky bugger because it mimics the signal from the B cell antigen receptor and CD40 so it activates the cells where EBV lives…is this a cause of autoimmunity. Could be. Is it better than anti-CD20 I don’t know.
Long-term Treatment Effects of Frexalimab on NfL, CXCL13, and Brain Volume Loss in Relapsing Multiple Sclerosis
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 frexalimab 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.
10.1212/WNL.0000000000216107
Efficacy and Safety of Frexalimab in Participants With Relapsing Multiple Sclerosis: 3-Year Results From the Phase 2 Open-label Extension
Patrick Vermersch1, Stephen Krieger2, Heinz Wiendl3, Cristina Granziera4, Yang Mao-Draayer5, Gary Cutter6, Oleksandr Kalbus7, Ivan Staikov8, Michal Dufek9, Xavier Montalban10, Stephane Saubadu11, Xiaodong Luo12, Brendan Smyth12, Biljana Djukic13, Philippe Truffinet11, Erik Wallstroem13, Gavin Giovannoni14
1University of Lille, Inserm U1172 LilNCog, CHU Lille, FHU Precise, Lille, France, 2Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY, United States, 3Department of Neurology and Neurophysiology, University of Freiburg, Freiburg, Germany; Brain & Mind Institute, University of Sydney, Sydney, Australia, 4Translational 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, 5Autoimmunity Center of Excellence, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States, 6Department of Biostatistics, UAB School of Public Health, Birmingham, AL, United States, 7Department of Neurology, Dnipro State Medical University, Dnipro, Ukraine, 8Clinic of Neurology and Sleep Medicine, Acibadem City Clinic University Hospital Tokuda, Sofia, Bulgaria, 9First Department of Neurology, St. Anne’s University Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic, 10Multiple Sclerosis Centre of Catalonia, Department of Neurology, Vall d’Hebron University Hospital, Barcelona, Spain, 11Sanofi, Gentilly, France, 12Sanofi, Morristown, NJ, United States, 13Sanofi, Cambridge, MA, United States, 14Queen Mary University of London, London, United Kingdom
Objective:To report efficacy and safety of frexalimab at Week (W)144 (3 years) in the phase 2 (NCT04879628) open-label extension (OLE) in participants with relapsing multiple sclerosis (pwRMS).
Background:Frexalimab is a second-generation anti-CD40L monoclonal antibody that inhibits the costimulatory CD40/CD40L pathway and may recalibrate immune networks involving adaptive and innate immunity. During the double-blind period of the phase 2 trial, frexalimab was well-tolerated and showed 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, 125 participants entered the OLE, during which placebo arm participants switched to the respective frexalimab arms. In the SC arms, the frexalimab dose was increased to 1800mg q4w to achieve pharmacokinetic comparability with the 1200mg q4w IV dose. By W112, all 57 SC participants switched to the 1800mg q4w dose, with W144 magnetic resonance imaging data available for 55 participants. Key endpoints included efficacy (number of Gd+ T1-lesions, new/enlarging T2-lesions, annualized relapse rate [ARR]) and safety outcomes.
Results:
As of June 24, 2025 (W144 cut-off), 100 participants (78%) remained on treatment. At W144, the total number of Gd+ T1-lesions (mean [SD]) remained low in all treatment groups (IV: 0.1 [0.3], placebo»IV: 0.3 [1.0]; SC: 0.0 [0.0] and placebo»SC: 0.1 [0.3]). New/enlarging T2-lesions monthly count also remained low through W144. Further, ARR (baseline–W144) was low in the original frexalimab-1200mg/IV arm, with 86% of participants remaining relapse-free. Frexalimab was well-tolerated through W144, with no new safety signals, stable lymphocyte counts and immunoglobulin levels.
Conclusions:
Frexalimab continues to exert sustained reduction in disease activity with favourable safety in pwRMS through 3 years, supporting its further development in phase 3 trials (FREXALT and FREVIVA) as a potential high-efficacy, non-lymphocyte-depleting therapy.
Source: multiple-sclerosis-research.org