Anti-CD40L antibody safe and effective in a phase 2 study

Efficacy and safety data at week 24 from the ongoing open-label part of the frexalimab phase 2 trial in relapsing MS were promising. This anti-CD40L antibody was well tolerated and continued to demonstrate a marked reduction of new MRI lesions. Phase 3 trials for frexalimab are already in preparation.

Frexalimab is a second-generation CD40L-targeting monoclonal antibody evaluated for the treatment of MS. It blocks the co-stimulatory CD40/CD40L pathway, which regulates both innate and adaptive immune responses. Frexalimab has the potential to block necessary co-stimulatory signals between B cells, T cells, and professional antigen-presenting cells, reducing inflammation without depletion of lymphocytes.

Key inclusion criteria of the phase 2 study (NCT04879628) were: 18–55 years of age; diagnosis of relapsing MS according to the 2017 revised McDonald criteria; ≥1 relapse within the previous year, or ≥2 relapses within 2 years, or ≥1 gadolinium-enhancing (Gd+) T1-lesion within 6 months. The 129 participants were randomised 2:2:1 to high-dose frexalimab, low-dose frexalimab, or a placebo. In the 12-week double-blind period, the high-dose group demonstrated an 89% reduction in new Gd+ lesions (P=0.0004) [1].

Of the 129 participants, 125 entered the ongoing open-label part of the study [2]. Efficacy endpoints were number of new Gd+ T1 lesions and new/enlarging T2 lesions. After 24 weeks, 96% of participants continuing high-dose frexalimab had no new Gd+ T1 lesions; 91% had no new/enlarging T2 lesions. In the low-dose frexalimab arm, these percentages were 80% and 74%, respectively. In participants who switched from placebo to high-dose frexalimab, the monthly count of new Gd+ T1 lesions decreased from 2.3 at week 12 to 0.4 at week 24 (and from 3.7 to 0.6, respectively, in those who switched to low-dose frexalimab). Circulating markers of chemokine ligand 13 and neurofilament light chain decreased over 24 weeks. There were no new safety concerns. The most common adverse events (≥10% in any group) were COVID-19 (of mild or moderate intensity), nasopharyngitis, and headache.

The authors concluded that their findings provide proof of concept for targeting CD40L in MS and support the development of frexalimab as a potential high-efficacy, non-depleting, MS therapy. Importantly, frexalimab was well tolerated; contrary to the first generation of anti-CD40 antibodies which were stunted by (platelet and hepatic) toxicities.

1. Vermersch P, et al. LB02, 2023 CMSC Annual Meeting, 31 May–3 June, Aurora, CO, USA.
2. Vermersch P, et al. Phase 2 efficacy and safety of frexalimab: 6-month results of a novel CD40L inhibitor in relapsing multiple sclerosis. P275, MSMilan 2023, 11–13 October, Milan, Italy.

 

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Posted on 4 December, 20234 December, 2023