Three-Year Extension Findings Reinforce Frexalimab’s Safety and Efficacy in Relapsing MS

New 3-year data from the phase 2 open-label extension (OLE) study (NCT04879628) of investigational frexalimab (Sanofi) demonstrated sustained reductions in disease activity and a favorable safety profile in patients with relapsing multiple sclerosis (RMS), further supporting the therapy’s advancement into ongoing phase 3 programs.¹

Presented at the 2026 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting in Charlotte, North Carolina, findings showed that MRI disease activity remained consistently low through 144 weeks of treatment, while most patients remained relapse-free during long-term follow-up.

For context, frexalimab is a second-generation anti-CD40L monoclonal antibody designed to inhibit the CD40/CD40L costimulatory pathway, a key mediator of adaptive and innate immune signaling implicated in MS pathophysiology. Unlike several currently approved high-efficacy MS therapies, frexalimab does not cause broad lymphocyte depletion, positioning it as a potential alternative approach for long-term immune modulation.²

“Frexalimab continues to exert sustained reduction in disease activity with favorable safety in [patients with RMS] through 3 years, supporting its further development in phase 3 trials,” lead investigator Patrick Vermersch, MD, PhD, vice president of research and head of one of the departments of neurology at the University of Lille, and colleagues wrote in the abstract.

The ongoing phase 2 OLE study followed participants who completed the original double-blind portion of the trial, where 129 patients had been randomized 4:4:1:1 to frexalimab 1200 mg intravenous (IV) every 4 weeks, frexalimab 300 mg subcutaneous (SC) every 2 weeks, or matching placebo.¹ Patients initially assigned placebo crossed over to active treatment after week 12, while SC dosing was later increased to 1800 mg every 4 weeks to achieve pharmacokinetic comparability with IV dosing.

As of the June 24, 2025 data cutoff, 100 participants (78%) remained on treatment at week 144. Across all treatment groups, the mean number of gadolinium-enhancing (Gd+) T1 lesions remained near zero. Patients continuously treated with IV frexalimab had a mean (SD) lesion count of 0.1 (0.3), while those who crossed from placebo to IV treatment recorded 0.3 (1.0) lesions. Participants treated with SC frexalimab similarly maintained minimal MRI activity, with lesion counts ranging from 0.0 to 0.1.¹

Investigators also reported persistently low new or enlarging T2 lesion counts through week 144. Annualized relapse rate (ARR) remained low from baseline through the 3-year period, with 86% of participants in the original IV treatment arm remaining relapse-free. Safety findings showed no new signals, with stable lymphocyte counts and immunoglobulin levels maintained throughout long-term treatment.

READ MORE: Ozanimod Preserves Multiple Sclerosis Cognition in New 3-Year Analysis

The latest findings build on previously reported 2-year OLE data presented at the 2025 American Academy of Neurology (AAN) Annual Meeting, where investigators observed continued suppression of MRI activity and low relapse rates after 96 weeks of treatment. At that analysis, 82% of participants remained on therapy and ARR in the IV treatment arm was reported at 0.08 (95% CI, 0.03-0.18), with 92% of patients relapse-free. The most common adverse events included nasopharyngitis, headache, and COVID-19.³

Additional biomarker analyses presented at the 2024 European Academy of Neurology (EAN) Congress demonstrated significant reductions in neurofilament light (NfL), a biomarker associated with neuroaxonal injury in MS. Patients treated with high-dose frexalimab experienced a 41% reduction in plasma NfL levels from baseline to week 48, while those receiving low-dose treatment demonstrated a 35% reduction.⁴

“As our science and diagnostic tools have evolved, so has our understanding of multiple sclerosis,” Vermersch previously said in a statement discussing the EAN data.⁴ “These data presented at EAN suggest that CD40L inhibition may reduce nerve cell damage in people with multiple sclerosis and reinforce the potential of frexalimab to slow or halt disease progression for people living with this disease.”

Frexalimab initially demonstrated efficacy in the placebo-controlled portion of the phase 2 trial published in the New England Journal of Medicine in 2024. In that study, adjusted mean counts of new Gd+ T1 lesions at week 12 were 0.2 and 0.3 in the high- and low-dose frexalimab groups, respectively, compared with 1.4 in pooled placebo recipients. Approximately 85% of treated participants at the 12-week mark had no new enhancing lesions versus 50% of placebo-treated patients.²

The agent is now being evaluated in several phase 3 studies. FREXALT-1 and FREXALT-2 are active-controlled studies comparing frexalimab with teriflunomide in relapsing MS, while FREVIVA is assessing the therapy in non-relapsing secondary progressive MS.⁵ More recently, investigators also introduced the phase 3 FREXCITE bridging study at the 2026 ACTRIMS Forum, designed to evaluate subcutaneous administration using an on-body delivery system in relapsing MS and non-relapsing SPMS populations.⁶

Click here for more CMSC 2026 coverage.

REFERENCES
1. Vermersch P, Granziera C, Mao-Draayer Y, et al. Efficacy and Safety of Frexalimab in Participants With Relapsing Multiple Sclerosis: 3-Year Results From the Phase 2 Open-Label Extension. Presented at: 2026 CMSC Annual Meeting; May 27-30, 2026; Charlotte, NC. Abstract DMT01.
2. Vermersch P, Granziera C, Mao-Draayer Y, et al. Inhibition of CD40L with frexalimab in multiple sclerosis. N Engl J Med. 2024;390:589-600. doi:10.1056/NEJMoa2309439
3. Vermersch P, Granziera C, Mao-Draayer Y, et al. Safety and Efficacy of Frexalimab from the Phase 2 Open-label Extension in Participants with Relapsing Multiple Sclerosis: 2-year Results. Presented at: 2025 American Academy of Neurology Annual Meeting; April 5-9, 2025; San Diego, CA. Abstract 001785.
4. Frexalimab new phase 3 data showed reduction of key biomarker of nerve cell damage in relapsing MS. News release. Sanofi. June 28, 2024. Accessed May 27, 2026. Sanofi Press Release
5. Krieger S, Vermersch P, Chitnis T, et al. Frexalimab in relapsing multiple sclerosis and non-relapsing secondary progressive multiple sclerosis: design of phase 3 FREXALT and FREVIVA trials. Presented at: 2024 Consortium of Multiple Sclerosis Centers Annual Meeting; May 29-June 2, 2024; Nashville, TN. Abstract DMT52.
6. Chitnis T, Mao-Draayer Y, Krieger S, et al. Frexalimab in Relapsing Multiple Sclerosis and Non-Relapsing Secondary Progressive Multiple Sclerosis: Design of the Phase 3 FREXCITE Trial. Presented at: 2026 ACTRIMS Forum; February 5-7, 2026; San Diego, CA. Abstract P110.