Frexalimab shows favourable long-term safety and efficacy

Frexalimab continued to show favourable safety and sustained reduction in disease activity in multiple sclerosis (MS) patients through 2.5 years. Frexalimab was well tolerated, and no new safety signals were reported. These results support further development in phase 3 trials. This humanised anti-CD40L antibody could become a novel MS treatment option that is highly efficacious without depleting lymphocytes.

The CD40/CD40L co-stimulatory pathway regulates adaptive and innate immune responses and plays a pivotal role in the pathogenesis of MS. The second-generation anti-CD40L antibody frexalimab inhibits this pathway, modifying T- and B-cell activation and innate immune-cell function, without depleting lymphocytes. In the 12-week double-blind period of a phase 2 trial (NCT04879628) in participants with relapsing MS, frexalimab showed favourable safety and efficacy [1]. Frexalimab 1,200 mg showed an 89% reduction in new gadolinium-enhancing (Gd+) T1 lesions versus placebo at week 12. The decrease in the number of lesions was sustained for 2 years in the open-label extension (OLE) [2].

Prof. Gavin Giovannoni (Royal London Hospital, UK) reported safety and efficacy results after 2.5 years in the phase 2 OLE [3]. In the original trial, 129 MS participants were randomised (4:4:1:1) to intravenous (IV) frexalimab 1,200 mg every 4 weeks, subcutaneous frexalimab 300 mg every 2 weeks, or a matching placebo. After 12 weeks, the placebo groups switched to the respective frexalimab arms. The subcutaneous dose was increased to 1,800 mg during the OLE to achieve an exposure comparable to the 1,200 mg IV dose.

At week 120, 102 participants (79%) were still on treatment. “An exceptionally good retention rate for this type of trial design”, noted Prof. Giovannoni. The total number of Gd+ T1 lesions remained very low in all treatment groups (see Figure).

Figure: Total number of Gd+ T1 lesions after 120 weeks [3].



BL, baseline; DBP, double-blind phase; Gd+, gadolinium enhancing; SC, subcutaneous; SEM, standard error of the mean.

The number of monthly new/enlarging T2 lesions also remained low with IV frexalimab 1,200 mg through week 120. The annualised relapse rate was 0.09 (95% CI 0.04‒0.19) in this group; 88% did not experience any relapse. EDSS remained stable. Frexalimab was well-tolerated throughout the study and OLE. The most common adverse events, occurring in ≥10% of participants, were nasopharyngitis, headache, COVID-19, and back pain.

1. Vermersch P, et al. N Engl J Med. 2024;390(7):589–600.
2. Vermersch P, et al. Neurology. 2025;104(7 Suppl 1):1785.
3. Vermersch P, et al. Safety and efficacy of frexalimab in participants with relapsing multiple sclerosis: 2.5-year results from the phase 2 open-label extension. O111, ECTRIMS 2025, 24–26 September 2025, Barcelona, Spain.

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Posted on 25 November 202525 November 2025