Long-Term Efficacy and Safety: Frexalimab Shows Sustained Success in 3-Year Phase 2 MS Data

At the Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting, researchers unveiled highly anticipated 3-year results from the phase 2 open-label extension of frexalimab, an investigational treatment for relapsing multiple sclerosis (RMS). The data, which follows participants through 144 weeks of treatment, suggests that frexalimb provides sustained reduction in disease activity with a favorable safety profile that distinguishes it from current lymphocyte-depleting therapies.¹

A New Mechanism of Action

Frexalimab represents a potential shift in the MS treatment landscape. It is a second-generation anti-CD40L monoclonal antibody designed to block the CD40/CD40L cosimulatory pathway. Unlike many high-efficacy MS disease-modifying therapies (DMTs) that work by depleting B-cells or T-cells, frexalimab is non-lymphocyte-depleting.^1,2

By inhibiting this pathway, the drug addresses the dysregulated immune networks involved in both adaptive and innate immunity. This mechanism is intended to reduce the migration of immune cells across the blood-brain barrier, decrease the release of inflammatory cytokines, and ultimately reduce demyelination and neurodegeneration.^1,2

The foundation for this research was laid in a landmark phase 2 trial with findings published in the New England Journal of Medicine. That initial double-blind, placebo-controlled study demonstrated that frexalimab (1200 mg intravenously every 4 weeks) achieved an 89% reduction in new gadolinium-enhancing (Gd+) T1 lesions at week 12 compared to placebo.²

Sustained MRI and Clinical Results

The new data presented at CMSC 2026 confirm that these early gains are durable. Through 144 weeks, the total number of Gd+ T1 lesions remained consistently low across all treatment arms. Similarly, the monthly count of new or enlarging T2 lesions and the overall T2 lesion volume remained suppressed throughout the 3-year period.¹

The clinical outcomes were equally robust. In the group receiving 1200 mg intravenously (IV), 86% of participants remained relapse-free over 3 years. The adjusted annualized relapse rate (ARR) for this group was remarkably low at 0.11. Furthermore, participants’ physical disability levels, measured by the Expanded Disability Status Scale, remained stable through week 144.¹

Safety and Tolerability Highlights

A key focus of the presentation was frexalimab’s safety profile, particularly its impact on the immune system. Because the drug does not deplete lymphocytes, mean lymphocyte counts remained stable over the 144-week duration. Additionally, levels of protective antibodies—immunoglobulin G (IgG) and M (IgM)—showed stability or only marginal decreases, which is a significant finding for long-term immune health.¹

Frexalimab was described as well-tolerated with no new or emerging safety signals. The most common adverse events (AEs) reported included COVID-19, nasopharyngitis, and headache. Although some serious AEs occurred, they were generally not considered related to the study drug, and treatment discontinuations due to AEs remained low.¹

The Road Ahead

The success of the phase 2 open-label extension has paved the way for an extensive phase 3 program. Ongoing trials include FREXALT, focusing on relapsing MS, and FREVIVA, targeting nonrelapsing secondary progressive MS. Additionally, the FREXCITE bridging study is evaluating whether a subcutaneous administration option can offer comparable efficacy to the intravenous route with added convenience for patients.¹

As frexalimab moves closer to potential regulatory approval, the CMSC 2026 data reinforce its potential as a high-efficacy, long-term option for those living with MS.

REFERENCES

1. Krieger S. Efficacy and safety of frexalimab in participants with relapsing MS: 3-year results from the phase 2 open-label extension. Presented at: Consortium of Multiple Sclerosis Centers (CMSC) 2026 Annual Meeting. May 28, 2026. Charlotte, NC.

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