Frexalimab CD40L inhibition slows the progression of multiple sclerosis

1. In this randomized controlled trial, multiple sclerosis patients who received frexalimab had fewer new gadolinium-enhancing T1 lesions compared to placebo groups.

2. Immune responses that are typically higher in multiple sclerosis patients were reduced in the participants taking frexalimab.

Evidence Rating Level: 1 (Excellent)

Study Rundown: The initiation of the adaptive and innate immune responses is regulated by the CD40-CD40L pathway. Throughout many studies on the CD40-CD40L pathway, it has been shown that it induces CD40L expression. Previous studies have also found genetic associations between a single-nucleotide polymorphism on CD40 and the risk of multiple sclerosis. The drug of interest, frexalimab, is a second-generation anti-CD40L IgG1 monoclonal antibody. Frexalimab has been Fc-engineered, allowing it to evade platelet aggregation normally triggered by Fc𝛾RIIa stimulation, thus overcoming the risk of thromboembolism. The trial consisted of a two-part study; the first was a double-blind, randomized- control, and the second was an open-label extension period. One biomarker of neuroaxonal damage in multiple sclerosis is plasma levels of NfL, which were lowered in patients treated with frexalimab. Plasma levels of CXCL13, an inflammatory activity, were also decreased in participants who received frexalimab, while they were increased in patients with active multiple sclerosis. The study was limited by the small sample size, the short length of time of the double-blind period, and the use of imaging endpoints for the main analyses. Overall, at week 12 of the trial, compared to week eight, treatment with frexalimab had a favorable effect, decreasing the number of new gadolinium-enhancing T1-weighted lesions when compared to the placebo.

Click here to read the study in the NEJM

In-Depth [randomized controlled trial]: This was a randomized controlled trial assessing the impact of frexalimab on the progression of multiple sclerosis. To be eligible for the study, individuals needed to be between the ages of 18 to 55 years, have a diagnosis of relapsing multiple sclerosis, have at least one relapse within the previous year, at least two relapses within the previous two years, or at least one active gadolinium-enhancing lesion during the six months before screening. Exclusion criteria included a diagnosis of primary or nonrelapsing progressive multiple sclerosis, currently receiving therapy for multiple sclerosis, relapse 30 days before randomization, pregnancy, use of certain medications, and any clinical condition that could adversely affect their participation. Participants were assigned to a 4:4:1:1 ratio, receiving 1200 mg of intravenous frexalimab every four weeks, 300 mg of subcutaneous frexalimab every two weeks, placebo administered intravenously, or placebo administered subcutaneously. The study took place between June 7, 2021, and September 21, 2022, and included 129 participants who matched the eligibility criteria, and 125 (97%) completed the double-blind period. Of the participants, 52 were assigned to receive 1200 mg frexalimab intravenously, 51 were assigned to receive 300 mg frexalimab subcutaneously, 12 were assigned to receive placebo intravenously, and 14 were assigned to receive the placebo subcutaneously. At week 12, the T1-weighted lesions were 0.2 (95% Confidence Interval [CI], 0.1 to 0.4) in the group receiving 1200 mg frexalimab, 0.3 (95% CI, 0.1 to 0.6) in the group receiving 300 mg frexalimab, compared to 1.4 (95% CI, 0.6 to 3.0) in the combined placebo groups. When compared to the placebo, the rate ratios from the model were 0.11 (95% CI, 0.03 to 0.38) in the 1200 mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300 mg group. Overall, using frexalimab to inhibit CD40L in those with multiple sclerosis over 12 weeks showed fewer gadolinium-enhancing T-1 weighted lesions relative to the control group.

Image: PD

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