• Patrick Vermersch, Cristina Granziera, Yang Mao-Draayer, Gary Cutter, Oleksandr Kalbus, Ivan Staikov, Michal Dufek, Stephane Saubadu, Raphael Bejuit, Philippe Truffinet, Biljana Djukic, Erik Wallstroem, Gavin Giovannoni, and Frexalimab Phase 2 Trial Group.
• From the University of Lille, INSERM Unité 1172, Lille Neuroscience and Cognition, Lille University Hospital, University Hospital Federation Precise, Lille (P.V.), and Sanofi, Chilly-Mazarin (S.S., R.B., P.T.) - both in France; Translational Imaging in Neurology Basel, Department of Biomedical Engineering, Faculty of Medicine, and the Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel and University of Basel, Basel, Switzerland (C.G.); the Department of Neurology, Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, and the Michigan Institute for Neurological Disorders, Farmington Hills (Y.M.-D.); the Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham (G.C.); the Department of Neurology, Dnipro State Medical University, Dnipro, Ukraine (O.K.); the Clinic of Neurology and Sleep Medicine, Acibadem City Clinic University Hospital Tokuda, Sofia, Bulgaria (I.S.); the First Department of Neurology, St. Anne's University Hospital, Brno, Czech Republic (M.D.); Sanofi, Cambridge, MA (B.D., E.W.); and Queen Mary University of London, London (G.G.).
• N. Engl. J. Med. 2024 Feb 15; 390 (7): 589600589-600.

BackgroundThe CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.MethodsIn this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.ResultsOf 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.ConclusionsIn a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).Copyright © 2024 Massachusetts Medical Society.

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