Positive phase II data of novel investigational anti-CD40L antibody frexalimab show significantly reduced disease activity in relapsing multiple sclerosis

Following 12 weeks of therapy, the number of new gadolinium-enhancing (GdE) T1-lesions was reduced by 89% and 79% in the higher- and lower-dose treatment arms, respectively, compared with placebo, meeting the study’s primary endpoint.

A substantial unmet need remains in MS for highly effective and well-tolerated treatment options that provide sustainable control of disease activity and disability progression, while minimizing risks. As the first second-generation anti-CD40L antibody to show efficacy in MS, frexalimab is thought to block the costimulatory CD40/CD40L cellular pathway necessary for adaptive (T and B cells) and innate (macrophages and dendritic cells) immune cell activation and function, without lymphocyte-depletion.

About the Phase II study ; The Phase II study was a randomized, double-blind, placebo-controlled trial evaluating frexalimab in patients with relapsing MS. In the trial, 129 patients with relapsing MS were randomized (4:4:1:1) to receive either higher or lower doses of frexalimab (n=52 and n=51, respectively) or matching placebo (n=12 and n=14, respectively; pooled for efficacy analyses) for 12 weeks (Part A).

After Week 12, patients receiving placebo switched to respective frexalimab arms and entered the open-label Part B, which is currently ongoing. The primary endpoint was the reduction in the number of new GdE T1-hyperintense MRI brain lesions after 12 weeks of treatment. Secondary endpoints included additional MRI-based efficacy measures as well as the safety, tolerability and pharmacokinetics of frexalimab. In the study, both groups receiving higher or lower doses of frexalimab had significant reductions in new GdE T1-hyperintense lesions after 12 weeks of treatment. At Week 12, high- and low-dose frexalimab significantly reduced the number of new GdE T1-lesions by 89% (95%CI: 62%-97%, p=0.0004) and 79% (95%CI: 44%-92%, p=0.0021), respectively, versus placebo (pooled dose groups). Additionally, both groups treated with frexalimab showed reductions in new or enlarging T2-lesions and total GdE T1-lesions. At Week 24, 96% of participants in the higher-dose frexalimab arm were free of new GdE T1-lesions. Early effects (Week 12) on MSIS-29 physical impact score (a patient-reported outcome) and plasma neurofilament light chain (NfL) levels will also be reported.

Frexalimab was well-tolerated, and 125 (97%) patients completed Part A and continued to the open-label Part B. The most common adverse events (?4%) in any frexalimab-treated group were COVID-19 (n=5 [9.8%] in the lower-dose group; all uncomplicated cases of mild or moderate intensity) and headache (n=1 [2.0%] and n=3 [5.8%] in the lower- and higher-dose group, respectively).

Gavin Giovannoni, MD, PhD, FCP, FRCP, FRCPath Chair of Neurology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London "Frexalimab has a unique mechanism of action, blocking the CD40/CD40L costimulatory pathway thought to regulate both adaptive and innate immune cell activation and function – a pathway that is pivotal in the pathogenesis of MS. We are thrilled with the results achieved with frexalimab in just 3 months, which shows that CD40L inhibition rapidly controls MS disease activity without lymphocyte depletion.”