The New England Journal of MedicineInhibition of CD40L with Frexalimab in Multiple Sclerosis

Frexalimab’s Role in Immune Modulation and MS Pathogenesis

In a meticulous phase 2 trial, researchers have embarked on evaluating the efficacy of frexalimab, a second-generation anti-CD40L monoclonal antibody, in the treatment of relapsing multiple sclerosis. This study stands out for its potential to redefine therapeutic strategies against a backdrop of immune system regulation, spotlighting the CD40–CD40L costimulatory pathway’s pivotal role in the disease’s pathogenesis.

Study Design:

• Participants: 129 individuals with relapsing multiple sclerosis were randomly assigned in a 4:4:1:1 ratio to different treatment groups.
• Treatment Regimens: Participants received either 1200 mg of frexalimab intravenously every 4 weeks (plus an 1800-mg loading dose) or 300 mg subcutaneously every 2 weeks (plus a 600-mg loading dose), against matching placebos.
• Duration and Follow-up: The primary endpoint was assessed at week 12, with all participants eligible for open-label frexalimab post the double-blind period.

Key Findings:

• Efficacy: Frexalimab showed a significant reduction in new gadolinium-enhancing T1-weighted lesions at week 12, with adjusted mean numbers of 0.2 and 0.3 for intravenous and subcutaneous administrations, respectively, versus 1.4 in the placebo group.
• Safety Profile: The most common adverse events reported were COVID-19 and headaches.
• Implications for Treatment: These results hint at frexalimab’s potential as a promising treatment avenue for multiple sclerosis, warranting further large-scale and long-term studies.

HCN Medical Memo
In this phase 2 trial, frexalimab’s inhibition of CD40L significantly reduced new gadolinium-enhancing T1-weighted lesions in multiple sclerosis patients, indicating the need for extended studies to confirm its long-term efficacy and safety.

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