CD40L Inhibitor Frexalimab Demonstrates Significant Reduction of Gadolinium-Enhancing Lesions in Multiple Sclerosis

Gavin Giovannoni, MD, PhD, FCP, FRCP, FRCPath

In the first phase 2 trial (NCT04879628) results of frexalimab (Sanofi), an investigational CD40L inhibitor, findings showed a pronounced reduction of new gadolinium-enhancing (GdE) lesions by 3 months in patients with relapsing multiple sclerosis (MS), with a safety profile that was well tolerated.^1,2

These data were presented as part of a late-breaker at the 2023 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 31 to June 3, in Aurora, Colorado. All told, frexalimab met the study’s primary end point, with an 89% (95% CI, 62-97; P = .0004) reduction in new GdE T1 lesions observed after 12 weeks of treatment in the high-dose group. Sanofi, the drug developer, plans to initiate pivotal trials assessing the agent in MS in early 2024.

"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,” Gavin Giovannoni, MD, PhD, FCP, FRCP, FRCPath, chair of neurology at the Blizard Institutes of Barts and The London School of Medicine and Dentistry, Queen Mary University of London, said in a statement.¹ "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."

The study, a randomized, double-blind, placebo-controlled trial, included 129 patients with relapsing MS who were randomly assigned 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) for 12 weeks. Of these, 125 completed the double-blind period and entered the open-label portion, which is currently ongoing.

Compared with pooled placebo, frexalimab low-dose reduced the number of new GdE T1-lesions by 79% (95% CI, 44-92; P = .0021). Additionally, both groups treated with the CD40L agent showed reductions in new or enlarging T2-lesions and total GdE T1-lesions. By week 24, 37 of 38 participants in the high-dose group had no new GdE lesions. Frexalimab demonstrated a safe profile as well, with the most common adverse events (AEs) recorded being COVID-19 (9.8% in the lower-dose group) and headache (higher-dose: 2.0%; lower-dose: 5.8%).

"Building on our 20 years of research and development in multiple sclerosis, we are committed to growing our robust pipeline of MS therapies by exploring multiple treatment approaches with unique MOAs that have the potential to slow or halt disability, which remains one of the greatest unmet medical needs in multiple sclerosis today," Erik Wallstrom, MD, PhD, global head of Neurology Development at Sanofi, said in a statement.

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Previous research has shown that CD40 and its ligand, CD40L, have a central role in the regulation of both humoral and cell-mediated immunity. CD40-CD40L interactions within the central nervous system (CNS) are critical determinants of disease development and progression. The lack of expression of CD40 by CNS-resident cells diminishes the intensity and duration of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis and reduces the degree of inflammatory cell infiltrates into the CND.

A relatively young research field, one 2021 study assessed the safety of toralizumab (IDEC Pharmaceuticals), an agent that binds specifically to human CD40L on T cells, thereby preventing CD40 signaling. The single-institution, open-label, dose-escalation, phase 1 trial included 12 patients with relapsing-remitting MS who received 4 doses of 1, 5, 10, or 15 mg/kg of humanized toralizumab intravenously every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years.³

Treatment with toralizumab resulted in an increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response. No serious AEs, including thromboembolic events, occurred during the 18-week defined study period. Patients on the therapy showed no exacerbation of the disease, as measured by clinical parameters, which included Expanded Disability Status Scale score, neuropsychological evaluation, and number of relapses, as well as MRI parameters.

REFERENCES
1. Positive phase 2 data of novel investigational anti-CD40L antibody frexalimab show significantly reduced disease activity in relapsing multiple sclerosis. News release. Sanofi. May 31, 2023. Accessed June 22, 2023. https://www.sanofi.com/en/media-room/press-releases/2023/2023-05-31-05-00-00-2678991
2. Vermersch P, Mao-Draayer Y, Kalbus O, et al. Frexalimba, a CD40L inhibitor, in relapsing multiple sclerosis: results from a randomized controlled phase 2 trial. Presented at: 2023 CMSC Annual Meeting; May 31 to June 3; Aurora, CO. LB02.
3. Fadul CE, Mao-Draayer Y, Ryan KA, et al. Safety and immune effects of blocking CD40 ligand in multiple sclerosis. Neurology. 2021;8(6). doi:10.1212/NXI.000000000001096