A phase II trial confirms the efficacy and safety of frexalimab and its ability to reduce disease activity in patients living with relapsing MS, with considerable benefit compared to placebo.
The CD40–CD40L (CD154) costimulatory pathway, which regulates adaptive and innate immune responses, has been implicated in the pathogenesis of multiple sclerosis (MS). Elevated levels of CD40L expression have been observed in individuals with MS, correlating with disease severity and disability. However, it is unclear if inhibiting this pathway may help MS patients.
Recently, the results of a phase II study using frexalimab to inhibit CD40L in MS patients were published in the New England Journal of Medicine.
Initial Results Confirm Frexalimab’s Efficacy
Previous attempts to target the CD40–CD40L pathway using first-generation anti-CD40L monoclonal antibodies were hindered by thromboembolic events. Frexalimab, a second-generation anti-CD40L humanized IgG1 monoclonal antibody, was developed with fragment crystallizable (Fc) engineering to mitigate the risk of thromboembolic events. This phase 2 trial aimed to evaluate the efficacy and safety of frexalimab in individuals with relapsing MS.
The trial enrolled 129 participants meeting specific eligibility criteria, including a diagnosis of relapsing MS, age between 18 and 55 years, and an Expanded Disability Status Scale (EDSS) score of no more than 5.5. Participants were randomized to receive either intravenous (loading dose of 1800 mg followed by 1200 mg every 4 weeks), subcutaneous frexalimab (loading dose of 600 mg followed by 300 mg every 2 weeks), or a matching placebo for a 12-week double-blind period, followed by an open-label extension period.
The primary endpoint of the trial was the number of new gadolinium-enhancing T1-weighted lesions on magnetic resonance imaging (MRI) at week 12 compared to week 8. Secondary endpoints included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety measures.
Results demonstrated a significant reduction in the number of new gadolinium-enhancing T1-weighted lesions in both frexalimab treatment groups compared to placebo. The adjusted mean number of new lesions was 0.2 in the 1200 mg intravenous group and 0.3 in the 300 mg subcutaneous group, compared to 1.4 in the pooled placebo group. Similar reductions were observed in secondary MRI endpoints.
The Bottom Line
Exploratory analyses showed potential benefits of frexalimab treatment on clinical endpoints such as relapse rate and patient-reported outcomes. Additionally, frexalimab treatment appeared to reduce plasma levels of biomarkers associated with neuroaxonal damage and inflammatory activity. Overall, frexalimab was well-tolerated, with no thromboembolic events reported during the trial. Adverse events were generally mild to moderate in severity. Importantly, no serious adverse events or deaths were attributed to frexalimab treatment.
In conclusion, this phase 2 trial provides encouraging evidence for the efficacy and safety of frexalimab in reducing disease activity in relapsing MS. Further research is warranted to confirm these findings and assess the long-term benefits and safety profile of frexalimab in larger cohorts of MS patients.
Source:
Vermersch, P., Granziera, C., Mao-Draayer, Y., Cutter, G., Kalbus, O. I., Staikov, I., Dufek, M., Saubadu, S., Bejuit, R., Truffinet, P., Djukic, B., Wallstroem, E., & Giovannoni, G. (2024). Inhibition of CD40L with Frexalimab in Multiple Sclerosis. The New England Journal of Medicine, 390(7), 589–600. https://doi.org/10.1056/nejmoa2309439
