MILAN — Treatment with investigational frexalimab, a novel CD40 ligand (CD40L) inhibitor, led to sustained reduction of MRI disease activity in relapsing multiple sclerosis (MS) at 6 months, follow-up data from a phase II study showed.
At 24 weeks, 96% of participants in the high-dose frexalimab group and 80% in the low-dose frexalimab group were free of new gadolinium-enhancing (Gd+) T1 lesions, reported Patrick Vermersch, MD, PhD, of the University of Lille in France.
The findings strengthen the rationale for targeting CD40L in MS and support developing frexalimab as a potential high-efficacy, non-lymphocyte-depleting therapy, Vermersch said at the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).
“During the last years, new drugs and new treatment algorithms have shown an improvement in our capacity to effectively decrease the risk of relapses and the accumulation of focal lesions into the central nervous system,” Vermersch told MedPage Today.
“These positive effects are mainly the consequences of the drugs on the adaptive immune cells — that is, T and B lymphocytes,” he continued. “These treatments have also shown a significant decrease in the risk of disability progression.”
“However, most of this effect is related to visible symptoms, such as motor symptoms or vision disturbances,” he observed. “We still have unmet needs concerning many less visible symptoms such as fatigue or cognitive disturbances, and also subtle changes in physical functions, which matter to patients. We know that these symptoms, in combination with some others, are related also to immune cells of the innate immunity, mainly the active microglial cells.”
Frexalimab is an anti-CD40L antibody that blocks the co-stimulatory CD40/CD40L pathway. It has the potential to decrease the interactions between B and T lymphocytes, and also among lymphocytes, macrophages, and microglial cells, Vermersch noted.
“The phase II trial has shown an early and very strong effect on the accumulation of focal lesions on MRI,” he said. “Beyond this effect, we believe that frexalimab has the capacity to better control all aspects of disability, consequences of relapses, and independent of [relapses] as ‘smoldering’ MS.”
In its phase II trial, the high-dose frexalimab treatment arm showed an 89% reduction in new Gd+ lesions during the double-blind period at week 12 compared with the pooled placebo arm. The study randomized 52 patients to high-dose frexalimab, 51 to low-dose frexalimab, 12 to high-dose matching placebo, and 14 to low-dose matching placebo.
The analysis at ECTRIMS-ACTRIMS reviewed data at week 24 from the ongoing open-label part of the phase II study. Of 129 randomized participants, 125 entered the open-label part. Mean baseline age of enrolled participants was about 37, and 66% were women.
Among participants who switched from placebo, the monthly count of new Gd+ T1 lesions fell from 1.9 at week 12 to 0.3 in the high-dose arm, and from 3.3 to 0.6 in the low-dose arm. The number of new or enlarging T2 lesions also declined, and plasma markers of inflammatory activity and axonal damage decreased over 24 weeks.
No new safety concerns emerged. The most common adverse events were mild or moderate COVID-19, nasopharyngitis, and headache.
Frexalimab is not a depleting agent, which is favorable for its safety, Vermersch noted. “However, safety and clinical efficacy remain to be demonstrated in the phase III trial,” he said.
“The mechanism of action could induce a shift from auto-aggressive T cells to a more tolerogenic profile, which is interesting in the early phases of MS,” Vermersch pointed out.
“The effect on microglial cells could lead to a better control of the progressive phase of the disease,” he added. “So frexalimab is promising for both relapsing-remitting MS and also for the progressive form.”
The phase II trial of frexalimab was funded by Sanofi.
Vermersch reported receiving honoraria and consulting fees from Biogen, Sanofi, Novartis, Teva, Merck, Roche, Imcyse, AB Science, and BMS-Celgene and research support from Novartis, Sanofi, and Roche.
European Committee for Treatment and Research in Multiple Sclerosis
Source Reference: Vermersch P, et al “Phase 2 efficacy and safety of frexalimab: 6-month results of a novel CD40L inhibitor in relapsing multiple sclerosis” ECTRIMS 2023; poster 275.