Published Phase 2 Findings Highlight CD40L Inhibitor Frexalimab as Potential Treatment for Multiple Sclerosis

Patrick Vermersch, MD, PhD

In a phase 2 study of patients with relapsing multiple sclerosis (MS) published in the New England Journal of Medicine, the use of frexalimab (Sanofi), a CD40L inhibitor, resulted in favorable reductions in the number of gadolinium-enhancing T1-weighted lesions relative to placebo. The company has already begun to initiate phase 3 studies assessing the agent in relapsing MS and non-relapsing secondary progressive MS.^1,2

The double-blind, placebo-controlled trial randomly assigned patients to either 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or matching placebos. Of the 129 participants included, 125 (97%) completed the 12-week double-blind period and entered the open-label period.

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.

Lead investigator Patrick Vermersch, MD, PhD, of the University of Lille, France, said in a statement, “These published Phase 2 results for frexalimab represent important data in not only the potential treatment of MS but to the broader MS community. Of note, at Week 12, both doses of frexalimab provided reduction of new lesions – a standard measure of active inflammation in MS – and was well-sustained over time and well tolerated, especially at the high dose of frexalimab where 96% of patients were free of new active lesions after 24 weeks of treatment."¹

Frexalimab is a second-generation antibody that blocks tha constimultory CD40/CD40L pathway which is important for activation and function of adaptive and innate immunity. After 24 weeks of treatment, results from the open-label period showed an unadjusted mean number of 0.1 (95% CI, 0.02-0.2) for new gadolinium-enhancing T1-weighted lesions for those in the 1200 mg group of frexalimab. In addition, 96% of these patients had no new such lesions; however, no definite conclusions were drawn considering it was a nonprespecified analysis.

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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.

Treatment with frexalimab resulted in reduced neurofilament light levels, with recorded 24% and 18% reductions in the 1200-mg and 300-mg group, respectively, at week 12. In addition, CXCL13 levels, a biomarker of inflammatory activity, appeared to decrease from baseline as compared with the pooled placebo group, with a 21% reduction in the 1200-mg group and a 30% reduction in the 300-mg group.

In terms of safety, adverse events (AEs) occurred in 29% of those in the frexalimab 1200-mg group, 45% of those in the frexalimab 300-mg group, and in 31% of those on placebo. One or more infections or infestations during the double-blind period were reported in 4 participants (8%) in the 1200-mg group, in 12 (24%) in the 300-mg group, and in 1 (4%) in the pooled placebo group. The study had no serious or severe AEs or deaths, as well as no cases of thromboembolic events.

Continued safety analyses showed that 2 participants in the 300-mg frexalimab group and 1 patient in the 1200-mg group had neurotropenia; although all patients recovered while staying on treatment. In addition, there was 1 patient in the 1200-mg frexalimab group who had an isolated asympomatic elevation in the alanine aminotransferase level on day 57 with no concomitant increase in bilirubin level and with slight elevations in the levels of aspartate aminotransferase and alkaline phosphatase. This event resolved, with the level reaching the normal range on day 85, while the participant continued to receive frexalimab.

REFERENCES
1. Phase 2 data published in NEJM show potential of frexalimab as high-efficacy therapy of relapsing MS. Sanofi. February 15, 2024. Accessed February 15, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-02-15-13-00-00-2829933
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