ECTRIMS 2025: Frexalimab shows long-term benefits for MS patients
Treatment seen to safely maintain disease control over 2.5 years in study
Frexalimab, a therapy Sanofi is developing for multiple sclerosis (MS) patients, led to sustained reductions in disease activity in people with relapsing forms of MS over more than two years of treatment, while continuing to show a favorable safety profile.
That’s according to new data from an ongoing, open-label extension of a global Phase 2 clinical trial (NCT04879628). The data showed that rates of new or enlarging lesions and of lesions with active inflammation remained low through 120 weeks, or about 2.5 years.
Relapse rates were also low — with 88% of participants on a high dose of frexalimab remaining relapse-free — and disability scores remained stable throughout the studies, the data showed.
“Frexalimab continues to show favorable safety and sustained reduction in disease activity in people with [relapsing forms of MS] through 2.5 years, supporting its further development in Phase 3 trials as a potential high-efficacy… therapy,” said Gavin Giovannoni, MD, PhD, a professor of neurology at Queen Mary University of London, who’s been involved in testing the experimental treatment.
Giovannoni shared the new data at this year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held Sept. 24-26, in Barcelona, Spain, and online. His presentation was titled “Safety and Efficacy of Frexalimab in Participants With Relapsing Multiple Sclerosis: 2.5-Year Results From the Phase 2 Open-label Extension.”
Frexalimab is a second-generation antibody that blocks the CD40/CD40L pathway, which drives the activation of multiple immune cells involved in MS inflammation.
By targeting the CD40L protein and preventing its interaction with the CD40 receptor, the therapy aims to dampen inflammatory responses without broadly depleting white blood cells, or lymphocytes. Lymphocyte depletion is the goal of many approved MS treatments, but it can raise the risk of infections.
‘Significant unmet need’ for therapies with long-term benefits
Another key feature of frexalimab is its dual action on both arms of the immune system. It targets adaptive immune cells like T-cells and B-cells — which drive the inflammatory attacks behind MS relapses and active lesions — as well as innate immune cells, such as macrophages, microglia, and dendritic cells. These innate immune cells are thought to drive the chronic inflammation that contributes to gradual disability progression in MS.
“There remains a significant unmet need in MS for therapies that offer lasting control of disability progression, while effectively reducing disease activity and maintaining an acceptable safety profile. Non-lymphocyte-depleting MS treatments may have advantages in protection against infections,” Erik Wallström, MD, PhD, global head of neurology at Sanofi, said in a written Q&A with Multiple Sclerosis News Today.
To assess frexalimab’s safety and effectiveness, Sanofi launched a proof-of-concept Phase 2 trial that enrolled 129 adults with relapsing forms of MS. Participants were randomly assigned to one of two doses of frexalimab — 1,200 mg administered monthly by into-the-vein infusions, or intravenously, or 300 mg given every other week subcutaneously, or via an under-the-skin injection — or a placebo for 12 weeks, or about three months.
In this part, both frexalimab groups had significantly fewer lesions with active inflammation (up to 89% less), as well as new and enlarging lesions (up to 92% less) than the placebo.
Following the main trial, the participants could join an open-label extension, in which those already on the experimental therapy continued their assigned regimen. Those on the placebo were given frexalimab either subcutaneously or intravenously.
In this part, the subcutaneous dose was increased to 1,800 mg monthly to achieve a similar exposure to the drug as in the intravenous group.
At ECTRIMS, Giovannoni shared data covering up to 120 weeks of treatment in the main trial and the extension part; 102 participants remained on treatment. These data showed that, regardless of treatment allocation in the main trial, all groups of patients had low numbers of active lesions and of new or enlarging lesions after 2.5 years — ranging from 0-0.2 lesions per patient, on average.
Lowest relapse rate seen for patients on high dose of frexalimab
Relapse rates were also low across groups, though the lowest relapse rate — 0.09 relapses per year — was observed in the patient group who were always on the high, intravenous dose of frexalimab.
“This observed annualized relapse rate is widely considered low and suggests a treatment is effective at reducing relapses,” Wallström said. He noted, however, that “relapses in this open-label Phase 2 extension study were not assessed by an adjudication committee,” meaning that some of the episodes noted may instead have been a temporary worsening of symptoms not related to the disease itself.
While patients on the subcutaneous injections only started receiving a dose that matched the intravenous infusions after entering the extension, Wallström said that this new regimen’s “efficacy in reducing MS disease activity — such as new or active lesions — … was similar to that seen with the intravenous regimen over 120 weeks.”
Wallström added: “Key outcomes … were kept comparably low in both the high-dose subcutaneous and intravenous groups. Both dosing methods in the study were generally well tolerated, with no new unexpected safety issues.”
In another presentation at ECTRIMS, Amit Bar-Or, MD, a neurologist at the University of Pennsylvania, shared that frexalimab treatment led to sustained reductions in neurofilament light chain (NfL). Indeed, this marker of nerve cell damage reached levels similar to those observed in healthy individuals after 120 weeks, the scientist noted.
“Overall, NfL decreased from [the study’s start] by 45% to 50% across treatment arms, indicating diminished [nerve cell] damage,” Bar-Or said.
His presentation was titled “Long-term Treatment Effect of Frexalimab on NfL and Plasma Biomarkers of Adaptive and Innate Immunity.”
Wallström noted that these findings “reinforce the potential of frexalimab” as a treatment for MS.
“We know that NfL levels may be related to acute inflammatory damage and chronic diffuse neuronal loss leading to disability progression, which makes it a key biomarker of nerve cell damage in people with MS,” Wallström said.
Frexalimab treatment also reduced markers of inflammation
In addition to NfL, researchers also observed several changes in markers of immune cell activity.
“Levels of immune cell biomarkers CXCL13 and CD27, associated with B-cell recruitment, T-cell activation, and MS disease activity, continued to decline through 120 weeks in frexalimab-treated participants, indicating sustained suppression of inflammation and adaptive immunity,” Wallström said.
Similarly, a biomarker of microglia and macrophage activity called TREM2 was also reduced, by as much as 39%.
“These results support the emerging understanding that … frexalimab may mitigate both acute and chronic neuroinflammation in MS,” Wallström said.
Frexalimab was also well tolerated through week 120. The most common adverse events included COVID-19, the common cold, headache, and back pain. Levels of lymphocytes and antibodies in the blood remained stable over time.
Together, the data presented at ECTRIMS support ongoing Phase 3 clinical trials that will continue to assess the therapy’s safety and efficacy, according to Sanofi.
The developer is currently sponsoring FREXALT (NCT06141473), which is enrolling about 1,600 adults with relapsing forms of MS, and FREVIVA (NCT06141486), which is seeking about 900 adults with nonrelapsing secondary progressive MS.
These results support the emerging understanding that … frexalimab may mitigate both acute and chronic neuroinflammation in MS.
In addition to frexalimab for MS, Sanofi is developing tolebrutinib, a once-daily oral therapy that’s believed to target the chronic inflammation contributing to disability progression among patients.
“Current research shows that relapse biology and disease progression biology are separate overlapping processes” Wallström said, noting that “there are no approved therapies for the unmet need of nonrelapsing progressive disease biology, where tolebrutinib is the only potential treatment to show efficacy to date.”
The company is seeking tolebrunitib’s approval by the U.S. Food and Drug Administration for treating nonrelapsing SPMS and for slowing disability accumulation independent of relapse activity in adults with MS. A decision was initially expected late last month, but was pushed to Dec. 28 to give the agency more time to review new data that was submitted.
“Sanofi is working closely with the FDA with the goal of making tolebrutinib available in the US as soon as possible,” Wallström said.
Note: The Multiple Sclerosis News Today team is providing live coverage of the 41st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Sept. 24-26. Go here to see the latest stories from the conference.
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