On 20 April, at the American Academy of Neurology (AAN) 2026 Annual Meeting, Sanofi presented three-year data from the open-label extension (OLE) part of the Phase II study of frexalimab (NCT04879628) in participants with relapsing multiple sclerosis (RMS), offering the most mature efficacy, safety, and biomarker dataset yet available for this investigational anti-CD40L monoclonal antibody (mAb).
The Phase II trial enrolled 129 participants, of whom 94% had relapsing remitting multiple sclerosis (RRMS), and 6% had secondary progressive multiple sclerosis (SPMS) with relapses. Following the 12-week double-blind period, 125 participants (97%) entered the OLE, with 100 participants (78%) remaining on treatment at the three-year cut-off (Week 144). This retention rate signalled a favourable tolerability profile.
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The magnetic resonance imaging (MRI) scans and clinical results at Week 144 were compelling. Gadolinium-enhancing (Gd+) T1 lesions and new or enlarging T2 lesions remained at nearly zero throughout the OLE across all treatment arms, sustained from the near-complete suppression first observed in the 12-week double-blind period, where frexalimab demonstrated an 89% reduction in new Gd+ T1 lesions versus pooled placebo. In the frexalimab 1,200mg intravenous arm, 86% of participants remained relapse-free over three years with an annualised relapse rate of 0.11, and Expanded Disability Status Scale (EDSS) scores remained low and stable throughout. The outcomes compare favourably with what is observed with the currently marketed anti-CD20 mAbs—Ocrevus (ocrelizumab), Kesimpta (ofatumumab), and Briumvi (ublituximab)—in similar trial populations.
The safety data over three years was generally positive. Specifically, frexalimab was well tolerated, no deaths were reported, serious adverse events were uncommon, and there were no emerging safety signals. Lymphocyte counts remained stable, and immunoglobulin (Ig) G and IgM levels showed only marginal decreases, remaining above the lower limits of normal throughout the follow-up period. This stands in direct contrast to the progressive immunoglobulin depletion observed with sustained anti-CD20 therapy, which key opinion leaders (KOLs) previously interviewed by GlobalData have increasingly cited as a driver of de-escalation decisions in older patients.
A companion poster presented at the same meeting reported the effects of frexalimab on plasma neurofilament light chain (NfL), CXCL13, and brain volume loss, providing an important mechanistic and neuroprotective dimension to the three-year efficacy data. Plasma NfL, a validated biomarker of neuroaxonal damage whose baseline values predict disability progression, declined from baseline by 35–49% across all treatment arms over 144 weeks, reaching levels comparable to those observed in healthy individuals. Plasma CXCL13, a B-cell chemoattractant implicated in leptomeningeal inflammation and a prognostic marker of multiple sclerosis (MS) disease activity, was reduced from baseline by 28–61% across all treatment arms, indicating sustained suppression of B-cell-mediated neuroinflammatory activity over the full three years. The frexalimab 1,200mg intravenous arm demonstrated the slowest rates of whole brain volume loss (0.28% per year), cerebral cortex volume loss (0.37% per year), and thalamic volume loss (0.52% per year) at Week 144, all falling within or approaching the range observed in healthy controls. The thalamus findings are particularly clinically significant since thalamic atrophy is an early and sensitive marker of neurodegeneration in MS and is strongly associated with cognitive decline.
The three-year clinical and biomarker data provide strong support for the ongoing Phase III program, which comprises FREXALT (NCT06141473) in RMS and FREVIVA (NCT06141486) in non-relapsing SPMS (nrSPMS). The FREXCITE bridging study (NCT07325292) is also underway to evaluate whether subcutaneous administration offers comparable outcomes to intravenous delivery. The nrSPMS indication is of particular strategic interest as it represents the largest unmet need in the MS market. Tolebrutinib is currently the only agent in late-stage development for nrSPMS with a positive Phase III readout, and for which frexalimab, despite its peripheral-only mechanism of action, may still offer neuroprotective benefit through modulation of the inflammatory cascade driving smoldering central nervous system (CNS) disease. The CXCL13 and NfL data from the Phase II OLE provided the first hints that this peripheral immunomodulatory strategy may have downstream consequences in the CNS that are consistent with neurodegeneration suppression.
Whether frexalimab’s favorable safety profile, particularly its preservation of immunoglobulin levels over time, will translate into a meaningful commercial advantage over the entrenched anti-CD20 class will ultimately depend on whether the Phase III efficacy readouts from FREXALT and FREVIVA continue to show the positive outcomes seen with the Phase II OLE. If the nrSPMS data from FREVIVA is positive, frexalimab could carve out a significant niche as the first non-immunoglobulin-depleting high-efficacy option for progressive MS patients who are most vulnerable to the infection burden associated with existing therapies. GlobalData forecasts frexalimab to generate the highest peak-year sales across the late-stage pipeline in MS across the seven major markets (US, France, Germany, Italy, Spain, UK, and Japan), reflecting the scale of the commercial opportunity if the Phase III program delivers.
