CD40L Inhibitor Frexalimab Demonstrates Significant Reduction of Neurofilament Light in Long-Term Extension

Patrick Vermersch, MD, PhD

New data from an open-label extension (OLE) period of a phase 2 study (NCT04879628) showed that treatment with Sanofi’s investigational agent frexalimab resulted in significant attenuation of neurofilament light (NfL), a biomarker of neuroaxonal damage, in patients with relapsing multiple sclerosis (MS). These findings further support the rationale for the therapy’s novel mechanism, inhibiting CD40L, in phase 3 studies to delay disability progression in this patient population.¹

In total, 97% (125 of 129) of participants who completed the 12-week double-blind portion of the study entered the OLE, where they either continued with low- or high-dose frexalimab or switched from placebo to either low- or high-dose frexalimab. Of these, 87% (112 of 129) remained in the study by the 48-week cut-off.

In the data, presented at the 10th Congress of the European Academy of Neurology (EAN), showed reductions in NfL across all 4 treatment groups by week 48, with the largest difference observed in the high-dose frexalimab group. From baseline to week 48, this group experienced a 41% in plasma NfL, going from 11.5 (SD, 1.9) pg/mL to 6.8 (SD, 2.0) pg/mL. Participants who continued to receive low-dose frexalimab showed a 35% reduction in plasma levels from baseline (12.4 [SD, 1.9] pg/mL) to week 48 (8.1 [SD, 1.7] pg/mL).

"As our science and diagnostic tools have evolved, so has our understanding of multiple sclerosis. We now know that NfL levels may be related to both acute inflammatory damage and chronic diffuse neuronal loss leading to disability progression, strengthening its position as a key biomarker of nerve cell damage in people with multiple sclerosis," Patrick Vermersch, MD, PhD, vice president of research and head of one of the departments of neurology at the University of Lille, said in a statement.¹ "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."

Over the years, NfL has been an emerging blood biomarker that can provide clinically useful information about prognosis and therapeutic efficacy in MS. From baseline to week 48, participants who eventually switched from placebo to high-dose frexalimab had a 24% reduction in plasma NfL. Following the crossover at week 12, this group saw a 39% reduction in such levels up to the 48-week time point. Participants in the placebo-low group who switched to low-dose frexalimab at week 12 experienced a 33% reduction in plasma NfL levels from baseline (11.8 [SD, 1.9] pg/mL) to week 48 (7.8 [SD, 2.1] pg/mL) and by 39% from week 12 when switched from placebo to low-dose frexalimab.

"People with multiple sclerosis need new high-efficacy treatment options that target disability progression, which remains an unmet need. These results, alongside the previously reported phase 2 efficacy and safety results, further show that frexalimab’s novel mechanism of action has the potential to deliver meaningful improvements for people living with this chronic and debilitating disease," Erik Wallström, MD, PhD, Global Head of Neurology Development at Sanofi, said in a statement.¹

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The double-blind, placebo-controlled portion of the trial, published in the New England Journal of Medicine, assigned patients to either 1200 mg of frexalimab administered every 4 weeks (with an 1800 mg loading dose), 300 mg of frexlaimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or matching placebos. At the conclusion of the 12-week period, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions relative to week 8 was 0.2 (95% CI, 0.1-0.4) in the 1200 mg frexalimab group, 0.3 (95% CI, 0.1-0.6) in the 300 mg frexalimab group, and 1.4 (95% CI, 0.6-3.0) in the pooled placebo group. Between the 2 frexalimab groups, 85% and 84% of patients, respectively, had no new gadolinium-enhancing lesions at week 12 vs 50% of those in the pooled placebo group.²

The adjusted mean total number of gadolinium-enhancing T1-weighted lesions at week 12, a secondary end point, was 0.2 (95% CI, 0.1-0.5) in the 1200-mg group and 0.3 (95% CI, 0.2-0.7) in the 300-mg group, as compared with 1.7 (95% CI, 0.8-3.7) in the pooled placebo group. On exploratory outcomes, those in the 1200-mg, 300-mg, and placebo groups recorded MSIS-29 physical domain scores of 24, 25, and 32, respectively. Overall, there was no meaningful between-group difference in the MSIS-29 psychological domain score, as well as no substantial change from baseline in the median change in EDSS score at 12 weeks in any trial group.

The CDL40 inhibitor is currently being assessed in 2 phase 3 trials, named FREXALT (NCT06141473) and FREVIVA (NCT06141486), that include patients with relapsing MS and non-relapsing secondary progressive MS. Both trials have begun enrollment and recruitment is currently ongoing. FREXALT is comprised of 2 independent (FREXALT-1 and FREXALT-2) phase 3, double-blind, double-dummy, active-controlled, parallel-group, event-driven trials comparing the efficacy and safety of frexalimab against comparator teriflunomide (Aubagio; Sanofi) in participants with relapsing MS. Each study includes 700 adults who are treated between 20-40 months, lasting up to 144 weeks.³

REFERENCES
1. Frexalimab new phase 3 data showed reduction of key biomarker of nerve cell damage in relapsing MS. News release. June 28, 2024. Accessed July 2, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-06-28-15-30-00-2906026
2. Vermersch P, Granziera C, Mao-Draayer Y, et al. Inhibition of CD40L with frexalimab in multiple sclerosis. NEJM. 2024;390:589-600. doi:10.1056/NEJMoa2309439
3. 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 CMSC Annual Meeting; May 29-June 2; Nashville, TN. ABSTRACT DMT52.