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Novel Anti-CD40L Antibody Slows New Brain Lesions in Relapsing MS

— Frexalimab shows promise in phase II study

MedpageToday
A computer rendering of the demyelination of a neuron

Frexalimab, an investigational second-generation CD40 ligand (CD40L) inhibitor, led to fewer new gadolinium-enhancing T1-weighted lesions in relapsing multiple sclerosis (MS), a phase II trial showed.

At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% CI 0.1-0.4) in MS patients who received 1,200 mg of frexalimab intravenously and 0.3 (95% CI 0.1-0.6) in those who received 300 mg of frexalimab subcutaneously compared with 1.4 (95% CI 0.6-3.0) in those who received placebo, reported Patrick Vermersch, MD, PhD, of the University of Lille in France, and co-authors.

Compared with placebo, rate ratios were 0.11 (95% CI 0.03-0.38) for the 1,200-mg group and 0.21 (95% CI 0.08-0.56) for the 300-mg group, the researchers wrote in the .

Secondary imaging endpoints generally were in the same direction as the primary endpoint, Vermersch and colleagues noted. Plasma levels of neurofilament light (NfL), a biomarker of axonal damage, appeared to decrease in the frexalimab groups. The most common adverse events that occurred in the trial were SARS-CoV-2 infection and headaches.

The paramount need in MS is for more effective therapy against disease progression, noted Stephen Hauser, MD, of the University of California San Francisco, in an .

Highly effective drugs in relapsing MS, like the anti-CD20 agents, have shown that when relapses are prevented, progression independent of relapse activity is uncovered, Hauser observed. "Thus, progression is present in most, if not all, patients with multiple sclerosis, regardless of where they are in the disease continuum," he wrote.

Frexalimab is an anti-CD40L antibody that blocks the co-stimulatory CD40/CD40L pathway. "Because of its role as a key co-stimulatory molecule that mediates interactions between T lymphocytes and B cells as well as other antigen-presenting cells, blockade of CD40-CD40L engagement is a rational therapeutic strategy in multiple sclerosis," Hauser suggested.

"Inhibitors of the CD40 pathway could down-regulate innate immunity in the central nervous system, a major contributor to progressive multiple sclerosis," he pointed out. "Although the current trial was neither designed nor powered to assess benefits against progressive multiple sclerosis, progression is where the true clinical value of frexalimab, and its place in the therapeutic armamentarium against multiple sclerosis, will need to be defined."

The included 129 people with relapsing MS; 125 completed the study's 12-week double-blind period. Mean age of participants was approximately 37, and 66% were women. About a third (30%) had gadolinium-enhancing lesions at baseline.

All participants had at least one relapse within the previous year, or at least two relapses in the previous 2 years, or at least one active gadolinium-enhancing lesion in the 6 months before screening. Patients with secondary progressive MS who were having relapses could enroll. Overall, 94% of participants had relapsing-remitting MS, and 6% had secondary progressive disease. The median Expanded Disability Status Scale (EDSS) score -- which ranges from 0 (normal exam) to 10 (death due to MS) -- was 2.5.

Participants were randomized to receive 1,200 mg of frexalimab administered intravenously every 4 weeks (after an 1,800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (after a 600-mg loading dose), or matching placebos for each treatment. After 12 weeks, all the participants could receive open-label frexalimab.

The primary endpoint was the number of new gadolinium-enhancing T1-weighted lesions on MRI at week 12 relative 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.

"The trial was too brief and small for conclusions regarding clinical outcomes, but over the 12-week double-blind period, no relapses occurred in the group that received 1,200 mg of frexalimab intravenously, and relapses occurred in approximately 4% of the participants in the group that received 300 mg of frexalimab subcutaneously and in the pooled placebo group," Vermersch and co-authors noted.

Study limitations included the trial's small sample size, short duration, and use of imaging endpoints. Preliminary data from the open-label extension period suggested frexalimab continued to have a sustained reduction of MRI activity at 6 months. Phase III studies in and are ongoing.

  • Judy George covers neurology and neuroscience news for ľֱ, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more.

Disclosures

This trial was supported by Sanofi.

Vermersch reported relationships with AB Science, Biogen, Bristol Myers Squibb, F.Hoffmann-La Roche, Imcyse, Janssen, Merck, Novartis, Sanofi, and Teva. Co-authors reported numerous relationships with industry.

Hauser reported relationships with Accure, Alector, Annexon, BD Biosciences, F. Hoffmann-LaRoche, Moderna, Neurona, NGM Bio, Novartis, and Pheno Therapeutics.

Primary Source

New England Journal of Medicine

Vermersch P, et al "Inhibition of CD40L with frexalimab in multiple sclerosis" N Engl J Med 2024; DOI: 10.1056/NEJMoa2309439.

Secondary Source

New England Journal of Medicine

Hauser SL "Silencing immune dialogue in multiple sclerosis" N Engl J Med 2024; DOI: 10.1056/NEJMe2314434.