New Mechanism Under Study for Relapsing MS May Offer Novel Pathways to Reducing Inflammation

Gavin Giovannoni, MD, PhD, shares his insight with the crowd at CMSC.
Image courtesy: Shmulik Almany

Novel mechanisms are being explored in an effort to fine-tune the treatment of multiple sclerosis (MS) by addressing the underlying pathogenesis of the disease. One such newer pathway under investigation involves drugs that block CD40 and CD40 ligand (CD40L), a set of costimulatory proteins expressed on antigen-presenting cells and T-cells respectively. At the 2023 CMSC Annual Meeting, on June 2, Gavin Giovannoni, MD, PhD, reported the first results from a phase 2 study (NCT04879628) of the anti-CD40L antibody, frexalimab (previously known as SAR441344; Sanofi), in relapsing multiple sclerosis.

Giovannoni, chair of neurology at the Blizard Institute of Barts and the London School of Medicine and Dentistry, presented the Whitaker Lecture at this year’s annual meeting, leading off an educational track that focuses on cutting-edge research in MS. His talk discussed the immunological underpinnings of MS, including the viral origins of the disease and his longstanding message that a broad approach for preserving brain health is essential to prevent irreversible disability from the disease.

Frexalimab is a second-generation monoclonal antibody within the class of anti-CD40L agents. This pathway mediates a wide range of activities on B cells, including induction of activation-associated surface antigen, entry into the cell cycle, isotype switching, Ig secretion, and memory generation. Blocking the CD40/CD40L pathway is thought to regulate both adaptive and innate immune cell activation and function, both pivotal in the pathogenesis of MS, Giovannoni said. In MS, the agent modifies both T- and B-cell activation to reduce inflammatory activity without the depletion of B cells.

Gavin Giovannoni, MD, PhD, addresses the room during his presentation.
Image courtesy: Shmulik Almany

In the 12-week placebo-controlled trial followed by an open-label extension, Giovannoni and colleagues randomly assigned 125 subjects between ages 18 and 55 with active MS to either high-dose frexalimab, low-dose frexalimab, or placebo. The primary end point was the number of new gadolinium-enhancing (Gd+) T1 lesions. After the 12-week blinded portion, participants transitioned to active treatment for the open-label phase.

In the blinded phase, those in the high-dose group exhibited a pronounced 89% reduction of new Gd+ T1 lesions. At week 24, 96% (44 of 46) in the high-dose frexalimab arm were free of Gd+ T1 lesions. The lower frexalimab dose also showed promising results, with a 79% reduction in new T1 lesions in 129 patients with relapsing MS. Both doses showed a significant reduction in the secondary end point of new and enlarging T2 lesions.

Frexalimab was well tolerated over the 12 weeks, with headache and COVID-19 reported in 4% or fewer individuals. No serious adverse events were reported. These safety findings represent an improvement over first-generation anti-CD40 agents, which have not made it off the ground as treatments for MS. Another anti-CD40, iscalimab, is being investigated in lupus, a disease with significant unmet treatment needs.

At a press briefing earlier in the week, Giovannoni told reporters that frexalimab would be administered as an intravenous infusion, although the subcutaneous route remains an option. By blocking the CD40L, frexalimab has the potential to address the acute and chronic inflammation that drives disability progression in MS. “This is the first report of randomized controlled phase 2 data for an anti-CD40L inhibitor in MS, suggesting that there is a therapy to target progression and prevent smoldering disease,” he said.